Patent Publication Number: US-11654161-B2

Title: Compositions and methods for neuralgenesis

Description:
RELATED APPLICATIONS 
     This application is a continuation application, filed under 35 U.S.C. § 120, of U.S. application Ser. No. 16/077,411, filed on Aug. 10, 2018, which is a national stage application, filed under 35 U.S.C. § 371, of International Stage Application No. PCT/US2017/017464, filed on Feb. 10, 2017, which claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62/294,112, filed Feb. 11, 2016, all of which are incorporated herein by reference in their entireties. 
    
    
     STATEMENT AS TO FEDERALLY SPONSORED RESEARCH 
     The invention was made with government support under the following grant awarded by the National Institute of Health (NIH): U18TR000547. The government has certain rights in the invention. 
    
    
     SEQUENCE LISTING 
     The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Oct. 10, 2020, is named 048317-518C01US_SL.txt and is 329,101 bytes in size. 
     BACKGROUND OF THE INVENTION 
     Simple neural in vitro systems do not reflect the physiology, cellular interactions, or genetics of mammalian brain tissue. Accordingly, there is an unmet need to develop human models of brain disorders and/or diseases. 
     SUMMARY OF THE INVENTION 
     The present invention provides brain microphysiological systems (BMPS) that can be produced from induced pluripotent stem cells (iPSCs). Furthermore, the invention provides for reproducible BMPS that differentiate into mature neurons and glial cells (astrocytes and oligodendrocytes) in the central nervous system. This model is electrophysiologically active in a spontaneous manner and may be reproduced with patient cells. The derivation of 3D BMPS from iPSCs has applications in the study and treatment of neurological diseases. 
     In an aspect, the disclosure provides an in vitro brain microphysiological system (BMPS), comprising two or more neural cell types aggregated into a spheroid mass, wherein the spheroid mass has a diameter that is less than about 500 μm and the in vitro BMPS is electrophysiologically active in a spontaneous manner. 
     In an embodiment, the two or more neural cell types comprise at least a mature neuron and glial cell. 
     In an embodiment, the two or more neural cell types further comprise cells selected from the group consisting of astrocytes, polydendrocytes, oligodendrocytes, and combinations thereof. 
     In an embodiment, the in vitro BMPS has neural characteristics selected from the group consisting of synaptogenesis, neuron-neuron interactions, neuronal-glial interactions, axon myelination, and combinations thereof. 
     In an embodiment, two or more neural cell types of the in vitro BMPS express one or more biomarker selected from the group consisting of GRIN1, GAD1, GABA, TH, LMX1A, FOXO1, FOXA2, FOXO4, CNP, MBP, TH, TUBIII, NEUN, SLC1A6, and any combination thereof. 
     In an aspect, the disclosure provides a synthetic neurological organ comprising two or more neural cell types aggregated into a spheroid mass, wherein the spheroid mass has a diameter that is less than 500 μm and the in vitro BMPS is electrophysiologically active in a spontaneous manner. 
     In an embodiment, the two or more neural cell types comprise at least a mature neuron and glial cells. 
     In an embodiment, the mature neuron and glial cells further comprise cells selected from the group consisting of astrocytes, polydendrocytes, oligodendrocytes, and combinations thereof. 
     In an embodiment, the synthetic neurological organ further comprises neural characteristics selected from the group consisting of synaptogenesis, neuron-neuron interactions, neuronal-glial interactions, axon myelination, and combinations thereof. 
     In an embodiment, the synthetic neurological organ mimics the microenvironment of the central nervous system (CNS). 
     In an aspect, the disclosure provides a method of reproducibly producing an in vitro brain microphysiological system (BMPS), comprising: inducing one or more pluripotent stem cell (PSC) types; differentiating the one or more PSC types to form one or more neural progenitor cell (NPC) types; exposing the one or more NPC types to gyratory shaking or stirring; and differentiating the one or more NPC types into one or more neural cell types aggregated into a spheroid mass, wherein the spheroid mass has a diameter that is less than 500 μm. 
     In an embodiment, the one or more pluripotent stem cells are selected from the group consisting of human or animal embryonic stem cells, iPSC, adult stem cells, fibroblasts, embryonic fibroblasts, peripheral blood mononuclear cells, neuronal precursor cells, mesenchymal stem cells, and combinations thereof. 
     In an embodiment, inducing further comprises: adding micro-glia or micro-glia precursor cells. 
     In an embodiment, the micro-glia or micro-glia precursor cells are selected from the group consisting of monocytes, human monocytes, pro-monocyte cell lines, iPSC-derived monocytes, hematopoetic stem cells, isolated microglia, immortalized microglia, and combinations thereof. 
     In an embodiment, gyratory shaking comprises constant or regular gyratory shaking or stirring for 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, or 8 or more weeks. 
     In an embodiment, the one or more growth factors are selected from the group consisting of GDNF, BDNF, GM-CSF, B27, basic FGF, basic EGF, NGF, CNTF, and any combination thereof. 
     In an aspect, the disclosure provides a method of cryopreserving an in vitro brain microphysiological system (BMPS), comprising: differentiating BMPS aggregates into one or more mature neurons; incubating the aggregates in a cryopreserving medium; and exposing the aggregates to freezing temperatures of −60° C. or colder. 
     In an embodiment, differentiating further comprises: inducing differentiation of one or more pluripotent stem cell types by incubation with one or more growth factors. 
     In an embodiment, the one or more pluripotent stem cells are selected from a group consisting of human or animal embryonic stem cells, iPSC, adult stem cells, fibroblasts, embryonic fibroblasts, peripheral blood mononuclear cells, neuronal precursor cells, mesenchymal stem cells, and combinations thereof. 
     In an embodiment, inducing further comprises: adding micro-glia precursor cells. 
     In an embodiment, micro-glia precursor cells are selected from the group consisting of monocytes, human monocytes, iPSC-derived monocytes, hematopoetic stem cells, pro-monocyte cell lines, isolated microglia, immortalized microglia, and combinations thereof. 
     In an embodiment, the one or more growth factors are selected from the group consisting of GDNF, BDNF, GM-CSF, B27, basic FGF, basic EGF, NGF, CNTF, and any combination thereof. 
     In an embodiment, the cryopreserving medium is a medium selected from the group consisting of regular cryopreservation medium (95% FBS and 5% DMSO), STEMdiff Neural Progenitor Freezing Medium (Stem Cells Technologies), solutions with cryoprotectants, and combinations thereof. 
     In an embodiment, exposing the aggregates to freezing temperatures further comprises freezing aggregates over a temperature gradient of about 1° C. per hour to below −60° C. over up to 48 hours. 
     In an embodiment, cryopreserving further comprises additives selected from the group consisting of DMSO, HES, glycerol, serum, and any combination or derivative thereof. 
     In an aspect, the disclosure provides a method of transporting a brain microphysiological system (BMPS) or mini-brain, comprising: producing the BMPS or mini-brain of claim  1 , incubating the BMPS or mini-brain at 37° C., and maintaining the temperature at 37° C. with constant application of heat while moving the BMPS or mini-brain. 
     In an embodiment, maintaining the temperature comprises use of heating pads, heaters, insulation, insulated boxes, heat packs, electric blankets, chemical pads, and combinations thereof. 
     In an aspect, the disclosure provides a method of studying a neurological disease or disorder comprising: producing an in vitro brain microphysiological system (BMPS); exposing the in vitro BMPS to conditions that replicate or induce the neurological disease or disorder; adding an agent to treat the neurological disease or disorder; and assessing the effect of the agent on the neurological disease or disorder. 
     In an embodiment, the neurological disease or disorder is selected from the group consisting of neurodegenerative disorder, muscular dystrophy, Parkinson&#39;s Disease, Huntington&#39;s Disease, Autism Spectrum Disorder and other neurodevelopmental disorders, Down&#39;s Syndrome, Multiple Sclerosis, Amyotrophic lateral sclerosis, brain cancer, encephalitis, infection, trauma, stroke, and paralysis. 
     In an aspect, the disclosure provides a method of treating a patient having a neurological disease or disorder, comprising: extracting a stem cell from the patient with a genetic background pre-disposed for the neurological disease or disorder; producing a brain microphysiological system (BMPS) or mini-brain with the genetic background; treating the BMPS or mini-brain with an agent targeting the neurological disease or disorder; and assessing the effect of the agent on the BMPS or mini-brain. 
     In an embodiment, the neurological disease or disorder is selected from the group consisting of neurodegenerative disorder, muscular dystrophy, Parkinson&#39;s Disease, Huntington&#39;s Disease, Autism Spectrum Disorder and other neurodevelopmental disorders, Down&#39;s Syndrome, Multiple Sclerosis, Amyotrophic lateral sclerosis, brain cancer, encephalitis, infection, trauma, stroke, and paralysis. 
     In an embodiment, the BMPS includes two or more neuronal cell types that include one or more genetically modified cells. The BMPS wherein the one or more genetically modified cells include one or more reporter genes. The BMPS further comprises one or more endothelial cells capable of forming a blood-brain-barrier. 
     In an embodiment, the synthetic neurological organ may include two or more neural cell types that include one or more genetically modified cells. The synthetic neurological organ including one or more genetically modified cells that include one or more reporter genes. The synthetic neurological organ further comprising one or more endothelial cells capable of forming a blood-brain-barrier. 
     In an aspect, the disclosure provides a method of reproducibly producing an in vitro brain microphysiological system (BMPS), comprising: exposing one or more NPC types to gyratory shaking or stirring; and differentiating the one or more NPC types into one or more neural cell types aggregated into a spheroid mass, wherein the spheroid mass has a diameter that is less than 500 μm. 
     In an embodiment, the spheroid mass has a diameter that is less than about 450 μm, 400 μm, 350 μm, or 300 μm, or a diameter that is between about 350 μm and about 300 μm, or a diameter that is between about 330 μm and about 300 μm, or a diameter that is about 310 μm. 
     In an embodiment, the two or more neural cell types of the in vitro BMPS express one or more biomarker selected from the group consisting of GRIN1, GAD1, GABA, TH, LMX1A, FOXO1, FOXA2, FOXO4, CNP, MBP, TH, TUBIII, NEUN, SLC1A6, and any combination thereof. 
     In an embodiment, the two or more neural cell types of the in vitro BMPS express one or more biomarker selected from the group consisting of GRIN1, GAD1, GABA, TH, LMX1A, FOXO1, FOXA2, FOXO4, CNP, MBP, TH, TUBIII, NEUN, SLC1A6, and any combination thereof. 
     In an embodiment, the two or more neural cell types of the in vitro BMPS express one or more biomarker selected from the group consisting of GRIN1, GAD1, GABA, TH, LMX1A, FOXO1, FOXA2, FOXO4, CNP, MBP, TH, TUBIII, NEUN, SLC1A6, and any combination thereof. 
     In an embodiment, inducing comprises a single PSC. 
     In an embodiment, the an in vitro brain microphysiological system (BMPS) may be produced according to the above described method. 
     It is also contemplated within the scope of the invention that the addition of other cells inside (see e.g.,  FIG.  6   ) and outside (see e.g.,  FIG.  7   ) the BMPS may be used to modify the structure/composition of the BMPS, such as, e.g., by forming a blood-brain-barrier. It is also contemplated that the BMPS described herein may include genetically modified pluripotent stem cells, or be combined with other organoids (see e.g., Example 11). 
     Definitions 
     By “agent” is meant any small compound, antibody, nucleic acid molecule, or polypeptide, or fragments thereof. 
     By “alteration” is meant a change (increase or decrease) in the expression levels or activity of a gene or polypeptide as detected by standard art known methods such as those described herein. As used herein, an alteration includes a 10% change in expression levels, preferably a 25% change, more preferably a 40% change, and most preferably a 50% or greater change in expression levels. 
     By “ameliorate” is meant decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease. 
     In this disclosure, “comprises,” “comprising,” “containing,” and “having” and the like may have the meaning ascribed to them in U.S. Patent law and may mean “includes,” “including,” and the like; “consisting essentially of” or “consists essentially” likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments. 
     “Detect” refers to identifying the presence, absence or amount of the analyte to be detected. 
     By “effective amount” is meant the amount of an agent needed to ameliorate the symptoms of a neurological disease relative to an untreated patient. The effective amount of active agent(s) used to practice the present invention for therapeutic treatment of a neurological disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an “effective” amount. 
     By “fragment” is meant a portion of a polypeptide or nucleic acid molecule. This portion contains, preferably, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the entire length of the reference nucleic acid molecule or polypeptide. A fragment may contain 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 nucleotides or amino acids, or more. 
     By “gene” is meant a locus (or region) of DNA that encodes a functional RNA or protein product, and is the molecular unit of heredity. 
     By “marker” is meant any protein or polynucleotide having an alteration in expression level or activity that is associated with a disease or disorder. 
     By “modulate” is meant alter (increase or decrease). Such alterations are detected by standard art known methods such as those described herein. 
     Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction. 
     By “reduces” is meant a negative alteration of at least 10%, 25%, 50%, 75%, or 100%. 
     By “reference” is meant a standard or control condition. 
     By “pluripotency” is meant stem cells with the potential to differentiate into any of the three germ layers: endoderm (e.g., interior stomach lining, gastrointestinal tract, the lungs), mesoderm (e.g., muscle, bone, blood, urogenital), or ectoderm (e.g., epidermal tissues and nervous system). However, one of skill in the art will understand that cell pluripotency is a continuum, ranging from the completely pluripotent cell that can form every cell of the embryo proper, e.g., embryonic stem cells and iPSCs (see below), to the incompletely or partially pluripotent cell that can form cells of all three germ layers but that may not exhibit all the characteristics of completely pluripotent cells. Induced pluripotent stem cells, commonly abbreviated as iPS cells or iPSCs are a type of pluripotent stem cell artificially derived from a non-pluripotent cell, typically an adult somatic cell, by inducing a “forced” expression of certain genes and transcription factors. These transcription factors play a key role in determining the state of these cells and also highlight the fact that these somatic cells do preserve the same genetic information as early embryonic cells. The ability to induce cells into a pluripotent state was initially pioneered using mouse fibroblasts and four transcription factors, Oct4, Sox2, Klf4 and c-Myc; —a process called reprogramming. The successful induction of human iPSCs derived from human dermal fibroblasts has been performed using methods similar to those used for the induction of mouse cells. These induced cells exhibit similar traits to those of embryonic stem cells (ESCs) but do not require the use of embryos. Some of the similarities between ESCs and iPSCs include pluripotency, morphology, self-renewal ability, a trait that implies that they can divide and replicate indefinitely, and gene expression. 
     By “stem cells” is meant undifferentiated biological cells that can differentiate into specialized cells and can divide (through mitosis) to produce more stem cells. They are found in multicellular organisms. In mammals, there are two broad types of stem cells: embryonic stem cells, which are isolated from the inner cell mass of blastocysts, and adult stem cells, which are found in various tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the body, replenishing adult tissues. In a developing embryo, stem cells can differentiate into all the specialized cells—ectoderm, endoderm and mesoderm (see induced pluripotent stem cells)—but also maintain the normal turnover of regenerative organs, such as blood, skin, or intestinal tissues. There are three known accessible sources of autologous adult stem cells in humans: 1. Bone marrow, which requires extraction by harvesting, that is, drilling into bone (typically the femur or iliac crest). 2. Adipose tissue (lipid cells), which requires extraction by liposuction. 3. Blood, which requires extraction through apheresis, wherein blood is drawn from the donor (similar to a blood donation), and passed through a machine that extracts the stem cells and returns other portions of the blood to the donor. Stem cells can also be taken from umbilical cord blood just after birth. Of all stem cell types, autologous harvesting involves the least risk. By definition, autologous cells are obtained from one&#39;s own body. 
     By “subject” is meant a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline. 
     As used herein, the terms “treat,” treating,” “treatment,” and the like refer to reducing or ameliorating a neurological disorder and/or symptoms associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated. 
     As used herein, the terms “prevent,” “preventing,” “prevention,” “prophylactic treatment” and the like refer to reducing the probability of developing a disorder or condition in a subject, who does not have, but is at risk of or susceptible to developing a disorder or condition. 
     Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive. Unless specifically stated or obvious from context, as used herein, the terms “a,” “an,” and “the” are understood to be singular or plural. 
     Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about. 
     A “therapeutically effective amount” is an amount sufficient to effect beneficial or desired results, including clinical results. An effective amount can be administered in one or more administrations. 
     By “GRIN1 polypeptide” (or glutamate ionotropic receptor NMDA type subunit 1) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. Q05586. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 1) 
                   
               
            
           
           
               
               
               
            
               
                   1 
                 mstmrlltla llfscsvara acdpkivnig avlstrkheq mfreavnqan krhgswkiql 
                   
               
               
                   
               
               
                  61 
                 natsvthkpn aiqmalsvce dlissqvyai lvshpptpnd hftptpvsyt agfyripvlg 
               
               
                   
               
               
                 121 
                 lttrmsiysd ksihlsflrt vppyshqssv wfemmrvysw nhiillvsdd hegraaqkrl 
               
               
                   
               
               
                 181 
                 etlleeresk aekvlqfdpg tknvtallme akelearvii lsaseddaat vyraaamlnm 
               
               
                   
               
               
                 241 
                 tgsgyvwlvg ereisgnalr yapdgilglq lingknesah isdavgvvaq avhelleken 
               
               
                   
               
               
                 301 
                 itdpprgcvg ntniwktgpl fkrvlmssky adgvtgrvef nedgdrkfan ysimnlqnrk 
               
               
                   
               
               
                 361 
                 lvqvgiyngt hvipndrkii wpggetekpr gyqmstrlki vtihqepfvy vkptlsdgtc 
               
               
                   
               
               
                 421 
                 keeftvngdp vkkvictgpn dtspgsprht vpqccygfci dlliklartm nftyevhlva 
               
               
                   
               
               
                 481 
                 dgkfgtqerv nnsnkkewng mmgellsgqa dmivapltin neraqyiefs kpfkyqglti 
               
               
                   
               
               
                 541 
                 lvkkeiprst ldsfmqpfqs tlwllvglsv hvvavmlyll drfspfgrfk vnseeeeeda 
               
               
                   
               
               
                 601 
                 ltlssamwfs wgvllnsgig egaprsfsar ilgmvwagfa miivasytan laaflvldrp 
               
               
                   
               
               
                 661 
                 eeritgindp rlrnpsdkfi yatvkqssvd iyfrrqvels tmyrhmekhn yesaaeaiqa 
               
               
                   
               
               
                 721 
                 vrdnklhafi wdsavlefea sqkcdlvttg elffrsgfgi gmrkdspwkq nvslsilksh 
               
               
                   
               
               
                 781 
                 engfmedldk twvryqecds rsnapatltf enmagvfmlv aggivagifl ifieiaykrh 
               
               
                   
               
               
                 841 
                 kdarrkqmql afaavnvwrk nlqdrksgra epdpkkkatf raitstlass fkrrrsskdt 
               
               
                   
               
               
                 901 
                 stgggrgalq nqkdtvlprr aiereegqlq lcsrhres 
               
            
           
         
       
     
     By “GRIN1 nucleic acid molecule” (or glutamate ionotropic receptor NMDA type subunit 1) is meant a polynucleotide encoding an GRIN1 polypeptide. An exemplary GRIN1 nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. NM_007327. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 2) 
                   
               
            
           
           
               
               
               
            
               
                    1 
                 gtcgccgcag cgtccggacc ggaaccagcg ccgtccgcgg agccgccgcc gccgccgccg 
                   
               
               
                   
               
               
                   61 
                 ggccctttcc aagccgggcg ctcggagctg tgcccggccc cgcttcagca ccgcggacag 
               
               
                   
               
               
                  121 
                 cgccggccgc gtggggctga gccccgagcc cccgcgcacg cttcagcgcc ccttccctcg 
               
               
                   
               
               
                  181 
                 gccgacgtcc cgggaccgcc gctccggggg agacgtggcg tccgcagccc gcggggccgg 
               
               
                   
               
               
                  241 
                 gcgagcgcag gacggcccgg aagccccgcg ggggatgcgc cgagggcccc gcgttcgcgc 
               
               
                   
               
               
                  301 
                 cgcgcagagc caggcccgcg gcccgagccc atgagcacca tgcgcctgct gacgctcgcc 
               
               
                   
               
               
                  361 
                 ctgctgttct cctgctccgt cgcccgtgcc gcgtgcgacc ccaagatcgt caacattggc 
               
               
                   
               
               
                  421 
                 gcggtgctga gcacgcggaa gcacgagcag atgttccgcg aggccgtgaa ccaggccaac 
               
               
                   
               
               
                  481 
                 aagcggcacg gctcctggaa gattcagctc aatgccacct ccgtcacgca caagcccaac 
               
               
                   
               
               
                  541 
                 gccatccaga tggctctgtc ggtgtgcgag gacctcatct ccagccaggt ctacgccatc 
               
               
                   
               
               
                  601 
                 ctagttagcc atccacctac ccccaacgac cacttcactc ccacccctgt ctcctacaca 
               
               
                   
               
               
                  661 
                 gccggcttct accgcatacc cgtgctgggg ctgaccaccc gcatgtccat ctactcggac 
               
               
                   
               
               
                  721 
                 aagagcatcc acctgagctt cctgcgcacc gtgccgccct actcccacca gtccagcgtg 
               
               
                   
               
               
                  781 
                 tggtttgaga tgatgcgtgt ctacagctgg aaccacatca tcctgctggt cagcgacgac 
               
               
                   
               
               
                  841 
                 cacgagggcc gggcggctca gaaacgcctg gagacgctgc tggaggagcg tgagtccaag 
               
               
                   
               
               
                  901 
                 gcagagaagg tgctgcagtt tgacccaggg accaagaacg tgacggccct gctgatggag 
               
               
                   
               
               
                  961 
                 gcgaaagagc tggaggcccg ggtcatcatc ctttctgcca gcgaggacga tgctgccact 
               
               
                   
               
               
                 1021 
                 gtataccgcg cagccgcgat gctgaacatg acgggctccg ggtacgtgtg gctggtcggc 
               
               
                   
               
               
                 1081 
                 gagcgcgaga tctcggggaa cgccctgcgc tacgccccag acggcatcct cgggctgcag 
               
               
                   
               
               
                 1141 
                 ctcatcaacg gcaagaacga gtcggcccac atcagcgacg ccgtgggcgt ggtggcccag 
               
               
                   
               
               
                 1201 
                 gccgtgcacg agctcctcga gaaggagaac atcaccgacc cgccgcgggg ctgcgtgggc 
               
               
                   
               
               
                 1261 
                 aacaccaaca tctggaagac cgggccgctc ttcaagagag tgctgatgtc ttccaagtat 
               
               
                   
               
               
                 1321 
                 gcggatgggg tgactggtcg cgtggagttc aatgaggatg gggaccggaa gttcgccaac 
               
               
                   
               
               
                 1381 
                 tacagcatca tgaacctgca gaaccgcaag ctggtgcaag tgggcatcta caatggcacc 
               
               
                   
               
               
                 1441 
                 cacgtcatcc ctaatgacag gaagatcatc tggccaggcg gagagacaga gaagcctcga 
               
               
                   
               
               
                 1501 
                 gggtaccaga tgtccaccag actgaagatt gtgacgatcc accaggagcc cttcgtgtac 
               
               
                   
               
               
                 1561 
                 gtcaagccca cgctgagtga tgggacatgc aaggaggagt tcacagtcaa cggcgaccca 
               
               
                   
               
               
                 1621 
                 gtcaagaagg tgatctgcac cgggcccaac gacacgtcgc cgggcagccc ccgccacacg 
               
               
                   
               
               
                 1681 
                 gtgcctcagt gttgctacgg cttttgcatc gacctgctca tcaagctggc acggaccatg 
               
               
                   
               
               
                 1741 
                 aacttcacct acgaggtgca cctggtggca gatggcaagt tcggcacaca ggagcgggtg 
               
               
                   
               
               
                 1801 
                 aacaacagca acaagaagga gtggaatggg atgatgggcg agctgctcag cgggcaggca 
               
               
                   
               
               
                 1861 
                 gacatgatcg tggcgccgct aaccataaac aacgagcgcg cgcagtacat cgagttttcc 
               
               
                   
               
               
                 1921 
                 aagcccttca agtaccaggg cctgactatt ctggtcaaga aggagattcc ccggagcacg 
               
               
                   
               
               
                 1981 
                 ctggactcgt tcatgcagcc gttccagagc acactgtggc tgctggtggg gctgtcggtg 
               
               
                   
               
               
                 2041 
                 cacgtggtgg ccgtgatgct gtacctgctg gaccgcttca gccccttcgg ccggttcaag 
               
               
                   
               
               
                 2101 
                 gtgaacagcg aggaggagga ggaggacgca ctgaccctgt cctcggccat gtggttctcc 
               
               
                   
               
               
                 2161 
                 tggggcgtcc tgctcaactc cggcatcggg gaaggcgccc ccagaagctt ctcagcgcgc 
               
               
                   
               
               
                 2221 
                 atcctgggca tggtgtgggc cggctttgcc atgatcatcg tggcctccta caccgccaac 
               
               
                   
               
               
                 2281 
                 ctggcggcct tcctggtgct ggaccggccg gaggagcgca tcacgggcat caacgaccct 
               
               
                   
               
               
                 2341 
                 cggctgagga acccctcgga caagtttatc tacgccacgg tgaagcagag ctccgtggat 
               
               
                   
               
               
                 2401 
                 atctacttcc ggcgccaggt ggagctgagc accatgtacc ggcatatgga gaagcacaac 
               
               
                   
               
               
                 2461 
                 tacgagagtg cggcggaggc catccaggcc gtgagagaca acaagctgca tgccttcatc 
               
               
                   
               
               
                 2521 
                 tgggactcgg cggtgctgga gttcgaggcc tcgcagaagt gcgacctggt gacgactgga 
               
               
                   
               
               
                 2581 
                 gagctgtttt tccgctcggg cttcggcata ggcatgcgca aagacagccc ctggaagcag 
               
               
                   
               
               
                 2641 
                 aacgtctccc tgtccatcct caagtcccac gagaatggct tcatggaaga cctggacaag 
               
               
                   
               
               
                 2701 
                 acgtgggttc ggtatcagga atgtgactcg cgcagcaacg cccctgcgac ccttactttt 
               
               
                   
               
               
                 2761 
                 gagaacatgg ccggggtctt catgctggta gctgggggca tcgtggccgg gatcttcctg 
               
               
                   
               
               
                 2821 
                 attttcatcg agattgccta caagcggcac aaggatgctc gccggaagca gatgcagctg 
               
               
                   
               
               
                 2881 
                 gcctttgccg ccgttaacgt gtggcggaag aacctgcagg atagaaagag tggtagagca 
               
               
                   
               
               
                 2941 
                 gagcctgacc ctaaaaagaa agccacattt agggctatca cctccaccct ggcttccagc 
               
               
                   
               
               
                 3001 
                 ttcaagaggc gtaggtcctc caaagacacg agcaccgggg gtggacgcgg cgctttgcaa 
               
               
                   
               
               
                 3061 
                 aaccaaaaag acacagtgct gccgcgacgc gctattgaga gggaggaggg ccagctgcag 
               
               
                   
               
               
                 3121 
                 ctgtgttccc gtcataggga gagctgagac tccccgcccg ccctcctctg ccccctcccc 
               
               
                   
               
               
                 3181 
                 cgcagacaga cagacagacg gacgggacag cggcccggcc cacgcagagc cccggagcac 
               
               
                   
               
               
                 3241 
                 cacggggtcg ggggaggagc acccccagcc tcccccaggc tgcgcctgcc cgcccgccgg 
               
               
                   
               
               
                 3301 
                 ttggccggct ggccggtcca ccccgtcccg gccccgcgcg tgcccccagc gtggggctaa 
               
               
                   
               
               
                 3361 
                 cgggcgcctt gtctgtgtat ttctattttg cagcagtacc atcccactga tatcacgggc 
               
               
                   
               
               
                 3421 
                 ccgctcaacc tctcagatcc ctcggtcagc accgtggtgt gaggcccccg gaggcgccca 
               
               
                   
               
               
                 3481 
                 cctgcccagt tagcccggcc aaggacactg atgggtcctg ctgctcggga aggcctgagg 
               
               
                   
               
               
                 3541 
                 gaagcccacc cgccccagag actgcccacc ctgggcctcc cgtccgtccg cccgcccacc 
               
               
                   
               
               
                 3601 
                 ccgctgcctg gcgggcagcc cctgctggac caaggtgcgg accggagcgg ctgaggacgg 
               
               
                   
               
               
                 3661 
                 ggcagagctg agtcggctgg gcagggccgc agggcgctcc ggcagaggca gggccctggg 
               
               
                   
               
               
                 3721 
                 gtctctgagc agtggggagc gggggctaac tggccccagg cggaggggct tggagcagag 
               
               
                   
               
               
                 3781 
                 acggcagccc catccttccc gcagcaccag cctgagccac agtggggccc atggccccag 
               
               
                   
               
               
                 3841 
                 ctggctgggt cgcccctcct cgggcgcctg cgctcctctg cagcctgagc tccaccctcc 
               
               
                   
               
               
                 3901 
                 cctcttcttg cggcaccgcc cacccacacc ccgtctgccc cttgacccca cacgccgggg 
               
               
                   
               
               
                 3961 
                 ctggccctgc cctcccccac ggccgtccct gacttcccag ctggcagcgc ctcccgccgc 
               
               
                   
               
               
                 4021 
                 ctcgggccgc ctcctccaga ctcgagaggg ctgagcccct cctctcctcg tccggcctgc 
               
               
                   
               
               
                 4081 
                 agcccagaac gggcctcccc gggggtcccc ggacgctggc tcgggactgt cttcaaccct 
               
               
                   
               
               
                 4141 
                 gccctgcacc ttgggcacgg gagagcgcca cccgcccgcc cccgccctcg ctccgggtgc 
               
               
                   
               
               
                 4201 
                 gtgaccggcc cgccaccttg tacagaacca gcactcccag ggcccgagcg cgtgccttcc 
               
               
                   
               
               
                 4261 
                 ccgtgcggcc cgtgcgcagc cgcgctctgc ccctccgtcc ccagggtgca ggcgcgcacc 
               
               
                   
               
               
                 4321 
                 gcccaacccc cacctcccgg tgtatgcagt ggtgatgcct aaaggaatgt cacgcagttt 
               
               
                   
               
               
                 4381 
                 tcaaaaaaaa aaaaaaaaaa 
               
            
           
         
       
     
     By “GAD1 polypeptide” (or glutamate decarboxylase 1) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. Q99259. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 3) 
                   
               
            
           
           
               
               
               
            
               
                   1 
                 masstpsssa tssnagadpn ttnlrpttyd twcgvahgct rklglkicgf lqrtnsleek 
                   
               
               
                   
               
               
                  61 
                 srlvsafker qssknllsce nsdrdarfrr tetdfsnlfa rdllpaknge eqtvqfllev 
               
               
                   
               
               
                 121 
                 vdillnyvrk tfdrstkvld fhhphqlleg megfnlelsd hpesleqilv dcrdtlkygv 
               
               
                   
               
               
                 181 
                 rtghprffnq lstgldiigl agewltstan tnmftyeiap vfvlmeqitl kkmreivgws 
               
               
                   
               
               
                 241 
                 skdgdgifsp ggaisnmysi maarykyfpe vktkgmaavp klvlftseqs hysikkagaa 
               
               
                   
               
               
                 301 
                 lgfgtdnvil ikcnergkii padfeakile akqkgyvpfy vnatagttvy gafdpiqeia 
               
               
                   
               
               
                 361 
                 dicekynlwl hvdaawgggl lmsrkhrhkl ngieransvt wnphkmmgvl lqcsailvke 
               
               
                   
               
               
                 421 
                 kgilqgcnqm cagylfqpdk qydvsydtgd kaiqcgrhvd ifkfwlmwka kgtvgfenqi 
               
               
                   
               
               
                 481 
                 nkclelaeyl yakiknreef emvfngepeh tnvcfwyipq slrgvpdspq rreklhkvap 
               
               
                   
               
               
                 541 
                 kikalmmesg ttmvgyqpqg dkanffrmvi snpaatqsdi dflieeierl gqdl 
               
            
           
         
       
     
     By “GAD1 nucleic acid molecule” (or glutamate decarboxylase 1) is meant a polynucleotide encoding an GAD1 polypeptide. An exemplary GAD1 nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. BC036552. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 4) 
                   
               
            
           
           
               
               
               
            
               
                    1 
                 agcgtgtggt agaggagaaa cgctgaaacc ggaccgaaac ctcgccctag gcttagcgat 
                   
               
               
                   
               
               
                   61 
                 ggctaaaaac cggctgggac aagagggagg caagcaacat tccgactcgc tgctttctgg 
               
               
                   
               
               
                  121 
                 ctgtctggag tgcaaggtga ctgtggttct tctctggcca agtccgaggg agaacgtaaa 
               
               
                   
               
               
                  181 
                 gatatgggcc tttttccccc tctcaccttg tctcaccaaa gtccctagtc cccggagcag 
               
               
                   
               
               
                  241 
                 ttagcctctt tctttccagg gaattagcca gacacaacaa cgggaaccag acaccgaacc 
               
               
                   
               
               
                  301 
                 agacatgccc gccccgtgcg ccctcccccc gctggcccac acgccggctg ctgagtgccc 
               
               
                   
               
               
                  361 
                 aatggggctt gtagcggctc ggctggaaaa tcgctcactg agcgctcccc tgtgctccta 
               
               
                   
               
               
                  421 
                 gcccagtccc ccacaccctt gcgtcttgta ctggccttgg acccccaccc cgaccccgac 
               
               
                   
               
               
                  481 
                 cccgcctcgt ctcggcgctt cactccaggt cgcgccgatg caccgccaga ctcgagagcg 
               
               
                   
               
               
                  541 
                 gcccagggct acgctccctg cgccccagta ccggagctag cgcgcacgtc tcctccgctg 
               
               
                   
               
               
                  601 
                 cccccacccc tgcgcacccc taccaggcag gctcgctgcc tttcctccct cttgtctctc 
               
               
                   
               
               
                  661 
                 cagagccgga tcttcaaggg gagcctccgt gcccccggct gctcagtccc tccggtgtgc 
               
               
                   
               
               
                  721 
                 aggaccccgg aagtcctccc cgcacagctc tcgcttctct ttgcagcctg tttctgcgcc 
               
               
                   
               
               
                  781 
                 ggaccagtcg aggactctgg acagtagagg ccccgggacg accgagctga tggcgtcttc 
               
               
                   
               
               
                  841 
                 gaccccatct tcgtccgcaa cctcctcgaa cgcgggagcg gaccccaata ccactaacct 
               
               
                   
               
               
                  901 
                 gcgccccaca acgtacgata cctggtgcgg cgtggcccat ggatgcacca gaaaactggg 
               
               
                   
               
               
                  961 
                 gctcaagatc tgcggcttct tgcaaaggac caacagcctg gaagagaaga gtcgccttgt 
               
               
                   
               
               
                 1021 
                 gagtgccttc aaggagaggc aatcctccaa gaacctgctt tcctgtgaaa acagcgaccg 
               
               
                   
               
               
                 1081 
                 ggatgcccgc ttccggcgca cagagactga cttctctaat ctgtttgcta gagatctgct 
               
               
                   
               
               
                 1141 
                 tccggctaag aacggtgagg agcaaaccgt gcaattcctc ctggaagtgg tggacatact 
               
               
                   
               
               
                 1201 
                 cctcaactat gtccgcaaga catttgatcg ctccaccaag gtgctggact ttcatcaccc 
               
               
                   
               
               
                 1261 
                 acaccagttg ctggaaggca tggagggctt caacttggag ctctctgacc accccgagtc 
               
               
                   
               
               
                 1321 
                 cctggagcag atcctggttg actgcagaga caccttgaag tatggggttc gcacaggtca 
               
               
                   
               
               
                 1381 
                 tcctcgattt ttcaaccagc tctccactgg attggatatt attggcctag ctggagaatg 
               
               
                   
               
               
                 1441 
                 gctgacatca acggccaata ccaacatgtt tacatatgaa attgcaccag tgtttgtcct 
               
               
                   
               
               
                 1501 
                 catggaacaa ataacactta agaagatgag agagatagtt ggatggtcaa gtaaagatgg 
               
               
                   
               
               
                 1561 
                 tgatgggata ttttctcctg ggggcgccat atccaacatg tacagcatca tggctgctcg 
               
               
                   
               
               
                 1621 
                 ctacaagtac ttcccggaag ttaagacaaa gggcatggcg gctgtgccta aactggtcct 
               
               
                   
               
               
                 1681 
                 cttcacctca gaacagagtc actattccat aaagaaagct ggggctgcac ttggctttgg 
               
               
                   
               
               
                 1741 
                 aactgacaat gtgattttga taaagtgcaa tgaaaggggg aaaataattc cagctgattt 
               
               
                   
               
               
                 1801 
                 tgaggcaaaa attcttgaag ccaaacagaa gggatatgtt cccttttatg tcaatgcaac 
               
               
                   
               
               
                 1861 
                 tgctggcacg actgtttatg gagcttttga tccgatacaa gagattgcag atatatgtga 
               
               
                   
               
               
                 1921 
                 gaaatataac ctttggttgc atgtcgatgg atttaacttc tcacaattgg ccaataggat 
               
               
                   
               
               
                 1981 
                 catctgcctt gctactgaac taatgactaa caaaggctgt gtcacgtggc atcccaacta 
               
               
                   
               
               
                 2041 
                 ttcagtaaac atgcatcatg gctgcctggg gaggtgggct gctcatgtcc aggaagcacc 
               
               
                   
               
               
                 2101 
                 accataaact caacggcata gaaagggcca actcagtcac ctggaaccct cacaagatga 
               
               
                   
               
               
                 2161 
                 tgggcgtgct gttgcagtgc tctgccattc tcgtcaagga aaagggtata ctccaaggat 
               
               
                   
               
               
                 2221 
                 gcaaccagat gtgtgcagga tacctcttcc agccagacaa gcagtatgat gtctcctacg 
               
               
                   
               
               
                 2281 
                 acaccgggga caaggcaatt cagtgtggcc gccacgtgga tatcttcaag ttctggctga 
               
               
                   
               
               
                 2341 
                 tgtggaaagc aaagggcaca gtgggatttg aaaaccagat caacaaatgc ctggaactgg 
               
               
                   
               
               
                 2401 
                 ctgaatacct ctatgccaag attaaaaaca gagaagaatt tgagatggtt ttcaatggcg 
               
               
                   
               
               
                 2461 
                 agcctgagca cacaaacgtc tgtttttggt atattccaca aagcctcagg ggtgtgccag 
               
               
                   
               
               
                 2521 
                 acagccctca acgacgggaa aagctacaca aggtggctcc aaaaatcaaa gccctgatga 
               
               
                   
               
               
                 2581 
                 tggagtcagg tacgaccatg gttggctacc agccccaagg ggacaaggcc aacttcttcc 
               
               
                   
               
               
                 2641 
                 ggatggtcat ctccaaccca gccgctaccc agtctgacat tgacttcctc attgaggaga 
               
               
                   
               
               
                 2701 
                 tagaaagact gggccaggat ctgtaatcat ccttcgcaga acatgagttt atgggaatgc 
               
               
                   
               
               
                 2761 
                 cttttccctc tggcactcca gaacaaacct ctatatgttg ctgaaacaca caggccattt 
               
               
                   
               
               
                 2821 
                 cattgaggga aaacataata tcttgaagaa tattgttaaa accttactta aagcttgttt 
               
               
                   
               
               
                 2881 
                 gttctagtta gcaggaaata gtgttctttt taaaaagttg cacattagga acagagtata 
               
               
                   
               
               
                 2941 
                 tatgtacagt tatacatacc tctctctata tatacatgta tagtgagtgt ggcttagtaa 
               
               
                   
               
               
                 3001 
                 tagatcacgg catgtttccc gctccaagag aattcacttt accttcagca gttaccgagg 
               
               
                   
               
               
                 3061 
                 agctaaacat gctgccaacc agcttgtcca acaactccag gaaaactgtt tttcaaaacg 
               
               
                   
               
               
                 3121 
                 ccatgtccta ggggccaagg gaaatgctgt tggtgagaat cgacctcact gtcagcgttt 
               
               
                   
               
               
                 3181 
                 ctccacctga agtgatgatg gatgagaaaa aacaccacca aatgacaagt cacaccctcc 
               
               
                   
               
               
                 3241 
                 ccattagtat cctgttaggg gaaaatagta gcagagtcat tgttacaggt gtactatggc 
               
               
                   
               
               
                 3301 
                 tgtattttta gagattaatt tgtgtagatt gtgtaaattc ctgttgtctg accttggtgg 
               
               
                   
               
               
                 3361 
                 tgggaggggg agactatgtg tcatgatttc aatgattgtt taattgtagg tcaatgaaat 
               
               
                   
               
               
                 3421 
                 atttgcttat ttatattcag agatgtacca tgttaaagag gcgtcttgta ttttcttccc 
               
               
                   
               
               
                 3481 
                 atttgtaatg tatcttattt atatatgaag taagttctga aaactgttta tggtattttc 
               
               
                   
               
               
                 3541 
                 gtgcatttgt gagccaaaga gaaaagatta aaattagtga gatttgtatt tatattagag 
               
               
                   
               
               
                 3601 
                 tgcccttaaa ataatgattt aagcatttta ctgtctgtaa gagaattcta agattgtaca 
               
               
                   
               
               
                 3661 
                 taaagtcata tatatggaaa tcctgttact taaatagcat ctgctcttct cttacgctct 
               
               
                   
               
               
                 3721 
                 ctgtctggct gtacgtctgg tgttctcaat gcttttctag caactgttgg ataataacta 
               
               
                   
               
               
                 3781 
                 gatctcctgt aattttgtag tagttgatga ccaatctctg ttactcgctt agctgaaacc 
               
               
                   
               
               
                 3841 
                 taaggcaaca tttccgaaga ccttctgaag atctcagata aagtgaccag gctcacaact 
               
               
                   
               
               
                 3901 
                 gtttttgaag aagggaaatt cacactgtgc gttttagagt atgcaagaag aatataaata 
               
               
                   
               
               
                 3961 
                 aataaaaata ttctccatgg agaatttgaa caaaaaaaaa aaaaaaa 
               
            
           
         
       
     
     By “GABA polypeptide” (or gamma-Aminobutyric acid) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. P30531. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 5) 
                   
               
            
           
           
               
               
               
            
               
                   1 
                 matngskvad gqistevsea pvandkpktl vvkvqkkaad lpdrdtwkgr fdflmscvgy 
                   
               
               
                   
               
               
                  61 
                 aiglgnvwrf pylcgknggg aflipyfltl ifagvplfll ecslgqytsi gglgvwklap 
               
               
                   
               
               
                 121 
                 mfkgvglaaa vlsfwlniyy iviiswaiyy lynsftttlp wkqcdnpwnt drcfsnysmv 
               
               
                   
               
               
                 181 
                 nttnmtsavv efwernmhqm tdgldkpgqi rwplaitlai awilvyfciw kgvgwtgkvv 
               
               
                   
               
               
                 241 
                 yfsatypyim liilffrgvt lpgakegilf yitpnfrkls dsevwldaat qiffsyglgl 
               
               
                   
               
               
                 301 
                 gslialgsyn sfhnnvyrds iivccinsct smfagfvifs ivgfmahvtk rsiadvaasg 
               
               
                   
               
               
                 361 
                 pglaflaype avtqlpispl wailffsmll mlgidsqfct vegfitalvd eyprllrnrr 
               
               
                   
               
               
                 421 
                 elfiaavcii syliglsnit qggiyvfklf dyysasgmsl lflvffecvs iswfygvnrf 
               
               
                   
               
               
                 481 
                 ydniqemvgs rpciwwklcw sfftpiivag vfifsavqmt pltmgnyvfp kwgqgvgwlm 
               
               
                   
               
               
                 541 
                 alssmvlipg ymaymfltlk gslkqriqvm vqpsedivrp engpeqpqag sstskeayi 
               
            
           
         
       
     
     By “GABA nucleic acid molecule” (or gamma-Aminobutyric acid) is meant a polynucleotide encoding an GABA polypeptide. An exemplary GABA nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. U76343. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 6) 
                   
               
            
           
           
               
               
               
            
               
                    1 
                 gtagcttcac taaggtggga tggatagcag ggtctcaggc acaaccagta atggagagac 
                   
               
               
                   
               
               
                   61 
                 aaaaccantg tatcacaaga tggagtttgt gctgtcagtg gctggggaga tcattggctt 
               
               
                   
               
               
                  121 
                 aggcaacgtc tggaggtttc cctatctctg ctacaaaaat gggggaggtg ccttcttcat 
               
               
                   
               
               
                  181 
                 cccctacctc gtcttcctct ttacctgtgg cattcctgtc ttccttctgg agacagcact 
               
               
                   
               
               
                  241 
                 aggccagtac actagccagg gaggcgtcac agcctggagg aagatctgcc ccatctttga 
               
               
                   
               
               
                  301 
                 gggcattggc tatgcctccc agatgatcgt catcctcctc aacgtctact acatcattgt 
               
               
                   
               
               
                  361 
                 gttggcctgg gccctgttct acctcttcag cagcttcacc atcgacctgc cctggggcgg 
               
               
                   
               
               
                  421 
                 ctgctaccat gagtggaaca cagaacactg tatggagttc cagaagacca acggctccct 
               
               
                   
               
               
                  481 
                 gaatggtacc tctgagaatg ccacctctcc tgtcatcgag ttctgggagc ggcgggtctt 
               
               
                   
               
               
                  541 
                 gaagatctct gatgggatcc agcacctggg ggccctgcgc tgggagctgg ctctgtgcct 
               
               
                   
               
               
                  601 
                 cctgctggcc tgggtcatct gctacttctg catctggaag ggggtgaagt ccacaggcaa 
               
               
                   
               
               
                  661 
                 ggtggtgtac ttcacggcca catttcctta cctcatgctg gtggtcctgt taattcgagg 
               
               
                   
               
               
                  721 
                 ggtgacgttg cctggggcag cccaaggaat tcagttttac ctgtacccaa acctcacgcg 
               
               
                   
               
               
                  781 
                 tctgtgggat ccccaggtgt ggatggatgc aggcacccag atattcttct ccttcgccat 
               
               
                   
               
               
                  841 
                 ctgtcttggg tgcctgacag ccctgggcag ctacaacaag taccacaaca actgctacag 
               
               
                   
               
               
                  901 
                 cggcaccagc tttgtggccg gctttgccat cttctccatc ctgggcttca tgtctcagga 
               
               
                   
               
               
                  961 
                 gcagggggtg cccatttctg aggtggccga gtcaggccct ggcctggctt tcatcgctta 
               
               
                   
               
               
                 1021 
                 cccgcgggct gtggtgatgc tgcccttctc tcctctctgg gcctgctgtt tcttcttcat 
               
               
                   
               
               
                 1081 
                 ggtcgttctc ctgggactgg atagccagtt tgtgtgtgta gaaagcctgg tgacagcgct 
               
               
                   
               
               
                 1141 
                 ggtggacatg taccctcacg tgttccgcaa gaagaaccgg agggaagtcc tcatccttgg 
               
               
                   
               
               
                 1201 
                 agtatctgtc gtctccttcc ctgtggggct gatcatgctc acagagggcg gaatgtacgt 
               
               
                   
               
               
                 1261 
                 gttccagctc tttgactact atgcggccag tggcatgtgc ctcctgttcg tggccatctt 
               
               
                   
               
               
                 1321 
                 cgagtccctc tgtgtggctt gggtttacgg agccaagcgc ttctacgaca acatcgaaga 
               
               
                   
               
               
                 1381 
                 catgattggg tacaggccat ggcctcttat caaatactgt tggctcttcc tcacaccagc 
               
               
                   
               
               
                 1441 
                 tgtgtgcaca gccacctttc tcttctccct gataaagtac actccgctga cctacaacaa 
               
               
                   
               
               
                 1501 
                 gaagtacacg tacccgtggt ggggcgatgc cctgggctgg ctcctggctc tgtcctcctg 
               
               
                   
               
               
                 1561 
                 gtctgcattc ctgcctggag cctctacaga ctcggaaccc tcaagggccc cttcagagag 
               
               
                   
               
               
                 1621 
                 agaatccgtc agctcatgtg cccagccgag gacctgcccc agcggaaccc agcaggaccc 
               
               
                   
               
               
                 1681 
                 tcggctcccg ccacccccag gacctcactg ctcagactca cagagctaga gtctcactgc 
               
               
                   
               
               
                 1741 
                 tagggggcag gcccttggat ggtgcctgtg tgcctggcct tggggatggc tgtggaggga 
               
               
                   
               
               
                 1801 
                 acgtggcaga agcagcccca tgtgttccct gcccccgacc tggagtggat aagacaagag 
               
               
                   
               
               
                 1861 
                 gggtattttg gagtccacct gctgagctgg aggcctccca ctgcaacttt tcagctcagg 
               
               
                   
               
               
                 1921 
                 ggttgttgaa cagatgtgaa aaggccagtg ccaagagtgt ccctcggaga cccttgaagg 
               
               
                   
               
               
                 1981 
                 c 
               
            
           
         
       
     
     By “TH polypeptide” (or Tyrosine Hydroxylase) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. NP_002692. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 7) 
                   
               
            
           
           
               
               
               
            
               
                   1 
                 mptpdattpq akgfrravse ldakqaeaim vrgqgapgps ltgspwpgta apaasytptp 
                   
               
               
                   
               
               
                  61 
                 rsprfigrrq sliedarker eaavaaaaaa vpsepgdple avafeekegk avlnllfspr 
               
               
                   
               
               
                 121 
                 atkpsalsra vkvfetfeak ihhletrpaq rpraggphle yfvrlevrrg dlaallsgvr 
               
               
                   
               
               
                 181 
                 qvsedvrspa gpkvpwfprk vseldkchhl vtkfdpdldl dhpgfsdqvy rqrrkliaei 
               
               
                   
               
               
                 241 
                 afqyrhgdpi prveytaeei atwkevyttl kglyathacg ehleafalle rfsgyredni 
               
               
                   
               
               
                 301 
                 pqledvsrfl kertgfqlrp vagllsardf laslafrvfq ctqyirhass pmhspepdcc 
               
               
                   
               
               
                 361 
                 hellghvpml adrtfaqfsq diglaslgas deeieklstl ywftvefglc kqngevkayg 
               
               
                   
               
               
                 421 
                 agllssygel lhclseepei rafdpeaaav qpyqdqtyqs vyfvsesfsd akdklrsyas 
               
               
                   
               
               
                 481 
                 riqrpfsvkf dpytlaidvl dspqavrrsl egvqdeldtl ahalsaig 
               
            
           
         
       
     
     By “TH nucleic acid molecule” (or Tyrosine Hydroxylase) is meant a polynucleotide encoding an TH polypeptide. An exemplary TH nucleic acid molecule is provided at NCBI Accession No. NG_008128. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 8) 
                   
               
            
           
           
               
               
               
            
               
                     1 
                 gcgggggggc agtgtgtgct ccagcatgtg tgtgtgtgtg tgcatgtaca cgtgtgcacc 
                   
               
               
                   
               
               
                    61 
                 tgtatcgcct gtgtgtgtgc atgtgatgtg tacacgtgtc atgcatgcac gcacatgtgt 
               
               
                   
               
               
                   121 
                 agtgtgtgct cgtgtgtggt gtgtgcctgt gtcatgtatg agcacacttg tatatgttgt 
               
               
                   
               
               
                   181 
                 gtgtactgtg tcatatatga gtgtgtttgc ctgtgtagtg catgcacatc cgtgtgtgca 
               
               
                   
               
               
                   241 
                 tctggtgtgt ccgtgggtca ttacgagtgc atcgtatgtg tatcgtgtac atgagtacac 
               
               
                   
               
               
                   301 
                 ttgtatgtgt ggtgtgtaca ggtgccatgt aagtgtgctt gtacatatat gcatgcatgt 
               
               
                   
               
               
                   361 
                 gtcatatgca tctgtgtgtg catgtgtgtg gtgcacacat gtgttatgtc tgagtgtgcc 
               
               
                   
               
               
                   421 
                 tgtatgtgtg ctatgtacac gtcatgtgtg agtgtgcttg catgtgcagt gtgtggatgc 
               
               
                   
               
               
                   481 
                 tgcttgtacc tgtggtgtgt acctgtgtca tgggtgctca cacgtgcatg gagtgttgtg 
               
               
                   
               
               
                   541 
                 tgtgtgcttg tgtgccccat gtgtgcatgt gtgtgtgcct cacacagatg cctgcatttg 
               
               
                   
               
               
                   601 
                 cctaggcact tgcaagagga caccatgctg gctctcaaag atcacagggc cacctgagcc 
               
               
                   
               
               
                   661 
                 ctgtgcacac cacagccagg ccatggctag accctgcaga gccacagggc gatgcctgtc 
               
               
                   
               
               
                   721 
                 agccagggga cccagaacac ctcctgggct cctccccagc acatggctgg gctcctccag 
               
               
                   
               
               
                   781 
                 caggcctgga tttgggaagg gcccgtggtg ggcaaggctg gtgctgggga gcaggcctgg 
               
               
                   
               
               
                   841 
                 tggcctcaga gactcgccct gtgggcggag cagcctcaca gccaggtcga agtcagcact 
               
               
                   
               
               
                   901 
                 ctgaccctgc cccacgcggg gagtgggcac cagtcccagg gcacagacgt gctgggtgat 
               
               
                   
               
               
                   961 
                 taatctgggt gattaagcct cgggctgaga ggctgttgag agagaacacg ctccattgtg 
               
               
                   
               
               
                  1021 
                 gagctggctc agcattcctt acggccatgg tggcaggggc tgtaaccaca gggacggcgg 
               
               
                   
               
               
                  1081 
                 aagtggtgga gggtggtggg gtatggaggg aagcccagag ggctccgtgc aggaaggtgg 
               
               
                   
               
               
                  1141 
                 agcctggtgc aatggagggg acagcaaggg ctcctcagac ctctgcgggg cccccactcc 
               
               
                   
               
               
                  1201 
                 cctggtcacc tgttttgtct ctgatctggc ctgggtcggc cctcactcct ggccccacct 
               
               
                   
               
               
                  1261 
                 catagccccc cctggtgggg ctccgctcca gcccttctcc ttcccagggg ccagtatgct 
               
               
                   
               
               
                  1321 
                 ggccccaggg gtctcttggg gcgtgacctc ggcctccaga gaaccctgtc ccagctctgc 
               
               
                   
               
               
                  1381 
                 ccttccctct ggggtctctg tagatgggac gctggtcaca gcagcctgtc tgatttgttc 
               
               
                   
               
               
                  1441 
                 cctgtggcct aggttcctga gccccacagt gccaggggat ggatgccacc ggatctttga 
               
               
                   
               
               
                  1501 
                 aagaccagtg tcaggccggg cgcagtggct cacgcctgta atcccagcac tttgggaggc 
               
               
                   
               
               
                  1561 
                 cgaggtgggc ggatcacgaa gtcaggagat cgagaccatc ctggctaaca cagtgaaacc 
               
               
                   
               
               
                  1621 
                 ccgtctccac taaaaataca aaaagttagc tgggcgtggt ggtgggcgcc tgtagtccca 
               
               
                   
               
               
                  1681 
                 gctacttggg aggctgaggc aggagaatgg cgtgaaccgg ggaggcggag cttgcagtga 
               
               
                   
               
               
                  1741 
                 gccgagatcg cgccattgca ctccagcctg ggtgacagag cgagactcgg tctcaaaaaa 
               
               
                   
               
               
                  1801 
                 aaagaaaaaa aggaaagacc agtgtcttgg gagttgggaa acctgggctg gagactcact 
               
               
                   
               
               
                  1861 
                 gcatgacccc tgagaagttg cacctcagaa cctcagtcct cgcatctgca gaatgggtct 
               
               
                   
               
               
                  1921 
                 gtgaacacct cagctgcccg aacgtggatg ccgcaggctg acccagcact gagctctacc 
               
               
                   
               
               
                  1981 
                 aagaccaggg gccagccgtg tgctccctcc aggcctgtgc ccagcgtgga gaggcctcgt 
               
               
                   
               
               
                  2041 
                 cccgtgggcg ctggagtgga gccttcctgg tgtttgtgga catctctgga gagggccaga 
               
               
                   
               
               
                  2101 
                 ggcaggtggg tgacacgggg catggctcaa tcatgggtgg tccagactgg agaggtaccc 
               
               
                   
               
               
                  2161 
                 tcgggctggg agcggggagg ctggccaggg tagacttttg gggcctccat ggataccctc 
               
               
                   
               
               
                  2221 
                 accatctgga atcggagagg ggcacggcac aaaggagggc ggggccaggg ccaggactgg 
               
               
                   
               
               
                  2281 
                 agtcgggggc acctctgtgc caacaggggc cttggatctg gggtacagca tggttccccg 
               
               
                   
               
               
                  2341 
                 gccctgaagg ggctggcgtg tgggacaggc ttcccaggaa tggataggca gggatggatg 
               
               
                   
               
               
                  2401 
                 ctgcctgatt ggggcgggag gctggaggca gggcaggtgc aggcacctga gggcagcact 
               
               
                   
               
               
                  2461 
                 cacctccaca ggggtccagg ggcctcccca gcctcagcac ctggcctggg ctcctgcctc 
               
               
                   
               
               
                  2521 
                 cagagagcct ggccccaagg aagagtctag taagcttagt tcccatcggg cttccatgaa 
               
               
                   
               
               
                  2581 
                 agcacaactg gcccggcagg aaaccgaatt aaaaagcaat atttgtatca gtggaagaca 
               
               
                   
               
               
                  2641 
                 tttgctgaaa ggttaaatcc acatccggca gtgtgggcca tgagcctccg gcgtggtgtt 
               
               
                   
               
               
                  2701 
                 catcaggcat gtctctcctc ctggcctggg cacctgagca ctggggccgc cctgggcaga 
               
               
                   
               
               
                  2761 
                 gctggggcgg ggtgctgggg ggcctggagc tgcctcaccg agggatcctc agcagccgac 
               
               
                   
               
               
                  2821 
                 cctgggggag gcaaatgaga ctctttctgg ggaccttgag gggagctcgg gggagccatg 
               
               
                   
               
               
                  2881 
                 cagagcttca ccaggcctgg acactgggca tggaggctgg gccacccaag ggccatcacc 
               
               
                   
               
               
                  2941 
                 agggactcag gtgggtgggc ctcagccctg ggtgacagaa gctcacgggc cgcagggcga 
               
               
                   
               
               
                  3001 
                 ggccagaggc tgagccttca ggctgaggtc ttggaggcaa atccctccaa cgcccttctg 
               
               
                   
               
               
                  3061 
                 agcaggcacc cagacctact gtgggcagga cccacaggag gtggaggcct ttggggaaca 
               
               
                   
               
               
                  3121 
                 ctgtggaggg gcatagcatc tccgagagag gacagggtct gcactgggtg ctgagagaca 
               
               
                   
               
               
                  3181 
                 gcaggggccg agcggtaggc ttccctgccc ccagggatgt tccagaggag cgcaagggag 
               
               
                   
               
               
                  3241 
                 gggcattaat atcgtggcaa gaaagggcag gcattgcaga gtgagcagcg acggaactgg 
               
               
                   
               
               
                  3301 
                 gttttgtggg atgcatagga gttcacccgg ataagaggtg ggtgaggaat gacactgcaa 
               
               
                   
               
               
                  3361 
                 accggggatc acggagcccc aaatccttct gggccaggaa gtgggaaggg ttggggggtc 
               
               
                   
               
               
                  3421 
                 ttccctttgc tttgactgag cactcagcct gcctgcagag ggcagcgagg agccacggag 
               
               
                   
               
               
                  3481 
                 gggtgtggga cagggatgcc atggctgaag cagttttagg aaaggtccca ggggctattg 
               
               
                   
               
               
                  3541 
                 ttgaagagag aacggggagc ggggagtccc acagctgaca ggagcagagt gggccctgag 
               
               
                   
               
               
                  3601 
                 agatgccagc tctggctgcc acagtgacca gccggggtag gccttcgaga agtcagggag 
               
               
                   
               
               
                  3661 
                 cgtctagggc ttctggctcc tgctgggccc agggtgtcat cttgggctgc caacaccaga 
               
               
                   
               
               
                  3721 
                 aagcccagca gatacaggaa gccccaagcc ctgtcggaaa cggttcttct ccaggaggga 
               
               
                   
               
               
                  3781 
                 cagcggtggc agcgttcagc cgcaggccat gcactctggg gccacgtcct tccctctgta 
               
               
                   
               
               
                  3841 
                 cagtccagca ttgtcaaggc aggctctggc catctctgct gaccccagag ggatggggag 
               
               
                   
               
               
                  3901 
                 gcctcccctt ccaccagaag ggccagaagc caccctgggc aggggcatca ctctccctgg 
               
               
                   
               
               
                  3961 
                 gtggggcagc ggctgggagc aggaggtgcc agtgggcgtg ggctggatgc gggtgcctgc 
               
               
                   
               
               
                  4021 
                 ggggcggaca tggaacttgg gggaggctct aggctggggt tgtcctcaag ggagttctca 
               
               
                   
               
               
                  4081 
                 ggtcacccca gggtcaccct caacccgggg cctggtgggg tagaggagaa actgcaaagg 
               
               
                   
               
               
                  4141 
                 tctctccaag gggaaggcat cagggccctc agcactgagg gacgtgcgtg ctctttaaag 
               
               
                   
               
               
                  4201 
                 aaggggccac aggaccccga gggaagccag gagctagcag tgggccatag aggggctgag 
               
               
                   
               
               
                  4261 
                 tggggtgggt ggaagccgtc cctggccctg gtcgccctgg caaccctggt ggggactgtg 
               
               
                   
               
               
                  4321 
                 atgcaggagg tggcagccat ttggaaacgc gtggcgtctc cttagagatg tcttcttcag 
               
               
                   
               
               
                  4381 
                 cctcccaggg tcctccacac tggacaggtg ggccctcctg ggacattctg gaccccacgg 
               
               
                   
               
               
                  4441 
                 ggcgagcttg ggaagccgct gcaagggcca cacctgcagg gcccgggggc tgtgggcaga 
               
               
                   
               
               
                  4501 
                 tggcactcct aggaaccacg tctatgagac acacggcctg gaatcttctg gagaagcaaa 
               
               
                   
               
               
                  4561 
                 caaattgcct cctgacatct gaggctggag gctggattcc ccgtcttggg gctttctggg 
               
               
                   
               
               
                  4621 
                 tcggtctgcc acgaggttct ggtgttcatt aaaagtgtgc ccctgggctg ccagaaagcc 
               
               
                   
               
               
                  4681 
                 cctccctgtg tgctctcttg agggctgtgg ggccaagggg accctggctg tctcagcccc 
               
               
                   
               
               
                  4741 
                 ccgcagagca cgagcccctg gtccccgcaa gcccgcgggc tgaggatgat tcagacaggg 
               
               
                   
               
               
                  4801 
                 ctggggagtg aaggcaatta gattccacgg acgagccctt tctcctgcgc ctccctcctt 
               
               
                   
               
               
                  4861 
                 cctcacccac ccccgcctcc atcaggcaca gcaggcaggg gtgggggatg taaggagggg 
               
               
                   
               
               
                  4921 
                 aaggtggggg acccagaggg ggctttgacg tcagctcagc ttataagagg ctgctgggcc 
               
               
                   
               
               
                  4981 
                 agggctgtgg agacggagcc cggacctcca cactgagcca tgcccacccc cgacgccacc 
               
               
                   
               
               
                  5041 
                 acgccacagg ccaagggctt ccgcagggcc gtgtctgagc tggacgccaa gcaggcagag 
               
               
                   
               
               
                  5101 
                 gccatcatgg taagagggca ggtaggtgcc cggcggccgc agtggaccgg agcccagggc 
               
               
                   
               
               
                  5161 
                 tggtgccagc tgcctctgct actccccagc ctggctggca gccccaggct cagggtccat 
               
               
                   
               
               
                  5221 
                 gcaaacccct gggacgcggc gtggatgtgg aggcctgggc acagcggcat cccctgtgcc 
               
               
                   
               
               
                  5281 
                 tggtgtttga gtccctgttg ggggagggtg aggtgatgcc tgtccctgtg tgtgcccctc 
               
               
                   
               
               
                  5341 
                 ttaggccgac ctctctcggg ggtcgtgtgg gtctctgtgt cttgtttcat cttgaatctt 
               
               
                   
               
               
                  5401 
                 aacgatcgga atgtggaaac aaatccatcc aaaaaatcca agatggccag aggtccccgg 
               
               
                   
               
               
                  5461 
                 ctgctgcacc cagcccccac cctactccca cctgcccctg cctccctctg ccccagctgc 
               
               
                   
               
               
                  5521 
                 cctagtcagc accccaacca gcctgcctgc ttggggaggc agccccaagg cccttcccag 
               
               
                   
               
               
                  5581 
                 gctctagcag cagctcatgg tggggggtcc tgggcaaata gggggcaaaa ttcaaagggt 
               
               
                   
               
               
                  5641 
                 atctgggctc tggggtgatt cccattggcc tgttcctccc ttatttccct cattcattca 
               
               
                   
               
               
                  5701 
                 ttcattcatt cattcattca ccatggagtc tgtgttccct gtgacctgca ctcggaagcc 
               
               
                   
               
               
                  5761 
                 ctgtgtacag gggactgtgt gggccaggct ggataatcgg gagcttttca gcccacagga 
               
               
                   
               
               
                  5821 
                 ggggtcttcg gtgcctcctt gggcactcag aaccttgggc tccctggcac atttaaaatg 
               
               
                   
               
               
                  5881 
                 ggtttttatt tatggacctt gattgaaatg tggtgtgagt tgtagcagtg tcatttccag 
               
               
                   
               
               
                  5941 
                 gtaccttctc agggacacag ggcgccctcc cccgtcctcc cccgccctcc cctaccctcc 
               
               
                   
               
               
                  6001 
                 cccaccaggc tccccatcag gcatcccctc cccagggcgc cccggggccc agcctcacag 
               
               
                   
               
               
                  6061 
                 gctctccgtg gcctggaact gcagccccag ctgcatccta cacccccacc ccaagggtaa 
               
               
                   
               
               
                  6121 
                 gtaagagggg actctgggag gggcttctgc tgctcccctt catgttccac aaccctggaa 
               
               
                   
               
               
                  6181 
                 gctcaggatg aagctgattc ttctcttaca aggggcccag agccttcttg ggagttcagc 
               
               
                   
               
               
                  6241 
                 tccaagggat gagccccagg tgtctgccaa gtccccctct gtccaggcct gggacggctc 
               
               
                   
               
               
                  6301 
                 tgggatcgag gggtcagagg cgctgagccc agggagagac acctgcgccc agagctatga 
               
               
                   
               
               
                  6361 
                 caaagggtgg agggatgaca aggcagccag gagcgggcgc ctgcggggtg gcacagaggg 
               
               
                   
               
               
                  6421 
                 gcagggcccg aggacaggtg tcctgatggg agtgtgagaa agggtcccct gtgcggcagc 
               
               
                   
               
               
                  6481 
                 caggagggta ggggggttgt tcactggggc cctgtggggg cagctccttc ctgagctgcc 
               
               
                   
               
               
                  6541 
                 gttccctccc cggcagccga tgccactgtc catcaagaca tcgccctctt cccatcacta 
               
               
                   
               
               
                  6601 
                 atccagttag cgcctggcct ggggatgagt gacacagcgt ctctgtctgt ctgctcgcca 
               
               
                   
               
               
                  6661 
                 cagagtgggg agcaggcgag caccttccca gcccccactc ctcccccacc accactgctt 
               
               
                   
               
               
                  6721 
                 ctgactgggc tgcccccatc gggaagggcg tgcaatgccc gcaggcacct cggctagcat 
               
               
                   
               
               
                  6781 
                 ctgccccagc aggcacacag taggcgctca aaaacgtgct ctcatcccct gcctctgtgt 
               
               
                   
               
               
                  6841 
                 gccatcagcg ctgcccgact gtgggaccag ctgtgggtgg aggtccccgg gtctcagcag 
               
               
                   
               
               
                  6901 
                 gtggaggagg catgggtgcc ccttgtcccc acagtccccg cggttcattg ggcgcaggca 
               
               
                   
               
               
                  6961 
                 gagcctcatc gaggacgccc gcaaggagcg ggaggcggcg gtggcagcag cggccgctgc 
               
               
                   
               
               
                  7021 
                 agtcccctcg gagcccgggg accccctgga ggctgtggcc tttgaggaga aggaggggaa 
               
               
                   
               
               
                  7081 
                 ggccgtgcta aacctgctct tctccccgag ggccaccaag ccctcggcgc tgtcccgagc 
               
               
                   
               
               
                  7141 
                 tgtgaaggtg tttgaggtga gctggtggcc ttcgtgtccc tggggcaagt tcacctgtgg 
               
               
                   
               
               
                  7201 
                 gtggggctgt gtgggctgag ttcctgaccc ctctatagca gaggtgcagc tgcccaggcc 
               
               
                   
               
               
                  7261 
                 cccgaggccg gcacaggatg cagcagggga gtctcaggcc tcagctcagc ccccatggca 
               
               
                   
               
               
                  7321 
                 tctagccaca cccccgtgtt tttgagggat cctgagccca cccctagggc tgaggctacc 
               
               
                   
               
               
                  7381 
                 aagccccact gtgcctcttg ccttgcccat cccctggatc cccctcaccc accatttccc 
               
               
                   
               
               
                  7441 
                 acgtgggggg ctcccagcag ggcagcacaa gaggcagggg cagggcagtg tgccctctcc 
               
               
                   
               
               
                  7501 
                 cacccaccca gcacagtggc tcaggtgacc actgattgca ttagtcactc cggccccact 
               
               
                   
               
               
                  7561 
                 gtgccccggg aggcaggtga cccagctccc ggaagaagct cccaaatgac attaaagcca 
               
               
                   
               
               
                  7621 
                 gactccccgc cccccagctc ccagagccag ttttgtggcc cgagggccac tgcgacccac 
               
               
                   
               
               
                  7681 
                 cgcccttgtt gctaggcaac aggaggtggg ggtggagcgg acccttctgg ccagtgtcct 
               
               
                   
               
               
                  7741 
                 ggacgctcag gggccagtga gactcagggc ccatcctaca aacctggatg aggccaccag 
               
               
                   
               
               
                  7801 
                 ggttgggggc accttctgac cagtggctga ggagccggac tgtgtggcat ggccttggga 
               
               
                   
               
               
                  7861 
                 cacacacacc gagccgccca gaaccaggtt aagcctcaag cggtgacaac tcctggttag 
               
               
                   
               
               
                  7921 
                 gcacgtaaca caaaatccaa cttgccagtg gcaaaccctg gcctggtggc cgacagctga 
               
               
                   
               
               
                  7981 
                 cctgagcctg gaagaacggg atctgtgtgc tgctagcaca aaagtcaagg gcagggcctg 
               
               
                   
               
               
                  8041 
                 gccagccagc cagatgtgcc tcctccccgc ccaccccacc ctctctctcc atctctgtct 
               
               
                   
               
               
                  8101 
                 ctttctcctt ctctctctct tcctgctttt gctccctaag acgtttgaag ccaaaatcca 
               
               
                   
               
               
                  8161 
                 ccatctagag acccggcccg cccagaggcc gcgagctggg ggcccccacc tggagtactt 
               
               
                   
               
               
                  8221 
                 cgtgcgcctc gaggtgcgcc gaggggacct ggccgccctg ctcagtggtg tgcgccaggt 
               
               
                   
               
               
                  8281 
                 gtcagaggac gtgcgcagcc ccgcggggcc caagggtgag gcggttttct gtccttgagg 
               
               
                   
               
               
                  8341 
                 gccaccaaat gaccttgaga ggctggggtg caggggctcc tgcaggggga ccctacagtg 
               
               
                   
               
               
                  8401 
                 accacgtggt ggtggcctgg ttccctctct gcgggctcca ctccgcaccc cgttttgcta 
               
               
                   
               
               
                  8461 
                 cacatccgtg tccgggcctg gggccactcc aggatccccc cgcagctctc acagccccgg 
               
               
                   
               
               
                  8521 
                 ctgcctctgc cccccggaag tcttgtaggg gaggctgctt caaggtgggt gacacagccc 
               
               
                   
               
               
                  8581 
                 cacggctccg agctcaccaa gatctcttcc tccatcaccc ataaagtccc ctggttccca 
               
               
                   
               
               
                  8641 
                 agaaaagtgt cagagctgga caagtgtcat cacctggtca ccaagttcga ccctgacctg 
               
               
                   
               
               
                  8701 
                 gacttggacc acccggtgag tggtgcgccc ctcactcagg cctcctgccc ctgatcacat 
               
               
                   
               
               
                  8761 
                 cccctaccct tagcccaacc ctggacagga gtctgtcggc tccaggagcc tccgtggcct 
               
               
                   
               
               
                  8821 
                 gtgcccccac cccagcacag cctcctgacc cgtgcatccc ctctgccctc agggcttctc 
               
               
                   
               
               
                  8881 
                 ggaccaggtg taccgccagc gcaggaagct gattgctgag atcgccttcc agtacaggca 
               
               
                   
               
               
                  8941 
                 gtgaggggcc cctgcgctcg ggacccagac tccgtcctgc aggctgacgc tggacctggg 
               
               
                   
               
               
                  9001 
                 gggtgggagg gaaggacaaa ggggaggacc catcttgtca ccagcatcag tgcctcctgc 
               
               
                   
               
               
                  9061 
                 caggcagctc tgctccaggg ctttccatgt ccccaaatcc cagtggggaa actgaggccc 
               
               
                   
               
               
                  9121 
                 aggggggcta gagcaacctg ccgaggccac atagccggct cacggcacag tcagctgggg 
               
               
                   
               
               
                  9181 
                 tgcaccctcc tgtccatcct ccaacccaaa ggcctcgctg cactaggcgg gtgtggacct 
               
               
                   
               
               
                  9241 
                 gtgcccagtg aagctccctc cctccctcct gcccttctca ctccccgagg ggacctgctg 
               
               
                   
               
               
                  9301 
                 accactggcc ccctccccag cggcgacccg attccccgtg tggagtacac cgccgaggag 
               
               
                   
               
               
                  9361 
                 attgccacct ggtgagacct ccgtgcagct aggggctggg gaggagcccg ggggatgcct 
               
               
                   
               
               
                  9421 
                 cctggaatcc tggcgtgtga gggccgcctc cagggacctt ggcacaacag gagagactaa 
               
               
                   
               
               
                  9481 
                 ggccgggaag aagagggact tgcagggctc agaatgttgg gttgggagga agaggctacc 
               
               
                   
               
               
                  9541 
                 catcctgtcg ggccatcccc agtgtgctga gggaccgccc ctcatggccc cctatcccct 
               
               
                   
               
               
                  9601 
                 gggattccct aaagccacca gcaaaagccc ctcccggggg cctgggtctt caggggtccc 
               
               
                   
               
               
                  9661 
                 caagaggcct gcgttggtag gggctcaggc aggcagaggc acccacagtt caggaggggg 
               
               
                   
               
               
                  9721 
                 gtttcgggca ctggggtggg gcattagagg gccctgagcc tggctgcccg caggaaggag 
               
               
                   
               
               
                  9781 
                 gtctacacca cgctgaaggg cctctacgcc acgcacgcct gcggggagca cctggaggcc 
               
               
                   
               
               
                  9841 
                 tttgctttgc tggagcgctt cagcggctac cgggaagaca atatccccca gctggaggac 
               
               
                   
               
               
                  9901 
                 gtctcccgct tcctgaaggg tgtgcccaga cgggaggggc gcagagccgg ggggccgggg 
               
               
                   
               
               
                  9961 
                 atggtcagcc aagcgcccca ccccagcgcg gctccagccc gtcccggctc ggcagtgacc 
               
               
                   
               
               
                 10021 
                 cgcgtggccc cttgcagagc gcacgggctt ccagctgcgg cctgtggccg gcctgctgtc 
               
               
                   
               
               
                 10081 
                 cgcccgggac ttcctggcca gcctggcctt ccgcgtgttc cagtgcaccc agtatatccg 
               
               
                   
               
               
                 10141 
                 ccacgcgtcc tcgcccatgc actcccctga gccgtgagtg cgcgccctgg ccgccagccc 
               
               
                   
               
               
                 10201 
                 gagggtgggg ggtgcgacgg gcggcccctc agcccccttc tccctcctac gcgcagggac 
               
               
                   
               
               
                 10261 
                 tgctgccacg agctgctggg gcacgtgccc atgctggccg accgcacctt cgcgcagttc 
               
               
                   
               
               
                 10321 
                 tcgcaggtac gccgcggcct cggagggagc cggggtcacc caggggctgg cttggcgccg 
               
               
                   
               
               
                 10381 
                 ggggcgggcg gggatcgatg tgcgggtggg tgaagtgtgc tgcctgctcc cgggccccgc 
               
               
                   
               
               
                 10441 
                 caaggaggct cggcgccccg agggtcgcgc ggcatagggc ggggctggag cggagcctcc 
               
               
                   
               
               
                 10501 
                 cacggcctgt gctgccacct gccggctacc tgggaacggc gcccacgggc ttaggaatgt 
               
               
                   
               
               
                 10561 
                 ggtcaaggag ggctgcctgg aggaggaggc ccggtggagg tgcggatcct gggcggccag 
               
               
                   
               
               
                 10621 
                 ggaaggtctc tgccgccagg gaagtgtccc agagacccct ggaggggctg ctgacacccc 
               
               
                   
               
               
                 10681 
                 cggtgccccc acctcgagca tgacccaggg ctgcctctcc ccatccttca tcctccctgc 
               
               
                   
               
               
                 10741 
                 tccacaggac attggcctgg cgtccctggg ggcctcggat gaggaaattg agaagctgtc 
               
               
                   
               
               
                 10801 
                 cacggtgggt tgacccctcc ctgcagggcc tggggtgtgg gtttgggggt ctgaatccag 
               
               
                   
               
               
                 10861 
                 gcctcaccct cttgccgtcc aggctgaggc ctctccttcc acccacgaat tgtgaccctc 
               
               
                   
               
               
                 10921 
                 accctggcct gcctgcatcc tggcctggcc tccctggggg tggtatcctg gtcacgggtg 
               
               
                   
               
               
                 10981 
                 accaggggct gcccggtggg cggcagctgt ctctgggctg atgctgcccg gcttccccgc 
               
               
                   
               
               
                 11041 
                 agctgtactg gttcacggtg gagttcgggc tgtgtaagca gaacggggag gtgaaggcct 
               
               
                   
               
               
                 11101 
                 atggtgccgg gctgctgtcc tcctacgggg agctcctggt gagagtctct ccttgctgca 
               
               
                   
               
               
                 11161 
                 gcccccagca gaggggcagg gctgggggac ggtgcaggga ggggacaggc tcccagtggg 
               
               
                   
               
               
                 11221 
                 aggaaactga ggcctggacc tccaggactc aggctctgtt tgggagaagg cttgtctctg 
               
               
                   
               
               
                 11281 
                 cccagtcctc accccacatt atcccaggcc tccgaaggcc cggcggggga gatgggggtg 
               
               
                   
               
               
                 11341 
                 actctaccca aggaacccac ccagcgtcag gccacggtgc cccagttccc tcggggacct 
               
               
                   
               
               
                 11401 
                 gggtgcagtg gagtcagtga tgccattggc ctcctgccag cactgcctgt ctgaggagcc 
               
               
                   
               
               
                 11461 
                 tgagattcgg gccttcgacc ctgaggctgc ggccgtgcag ccctaccaag accagacgta 
               
               
                   
               
               
                 11521 
                 ccagtcagtc tacttcgtgt ctgagagctt cagtgacgcc aaggacaagc tcaggtgggc 
               
               
                   
               
               
                 11581 
                 taggctgcta gggcaagccc cccatggtgc ccccaaactg ggccagccag gccttccttc 
               
               
                   
               
               
                 11641 
                 tggccttgag cagggctgga cctgtgagcc caggtcacag atgagaaaac cgacccctgg 
               
               
                   
               
               
                 11701 
                 ttgcagcagc ccccacacag cagggacacc atccgtgaga aggaccccag cgtctgggga 
               
               
                   
               
               
                 11761 
                 ggggcagacc tacaggactg ggggctgctg ggtggccggg tcaaggccag tcttggaggt 
               
               
                   
               
               
                 11821 
                 gctgacagag cctgagcttt gtgaggacgt cctgtggaac ctgtcccggc cccctgccct 
               
               
                   
               
               
                 11881 
                 gggatgggga gaagtcaggg ggatagacag agtcaaggtg ggggacaggg cgggagtggg 
               
               
                   
               
               
                 11941 
                 gtccccaggg ctgggggcct ttggtgcagt gaccagagtg tcaggagagg ggagcaaagc 
               
               
                   
               
               
                 12001 
                 cctctagcct catcctcata aaaggtctca tcattttccc tccagcctct tatgcactgg 
               
               
                   
               
               
                 12061 
                 ggaaactgag gccaggggct atgtgtccag cggacagggg tgctgaattc cacccacagg 
               
               
                   
               
               
                 12121 
                 cttagggata tggtcaagga aagcttcctg gaggaggccc agtggaggtt cagggaggga 
               
               
                   
               
               
                 12181 
                 tggggtgccc ggcagtctct agtggaaaag gcgcctagcc tatctccccc atgaaccccc 
               
               
                   
               
               
                 12241 
                 tcacccagcc ctggaagagg cctcagtgtc ccgcctgtga ccagttggct cagaaaagcc 
               
               
                   
               
               
                 12301 
                 ctgggagctc tgagccactg tgaaggtgga aacgcggccc ctggcctccc ctctcctgga 
               
               
                   
               
               
                 12361 
                 ggctgcagac tctgcccgcc agttgacgag ggctctgccg ctctcctccc caggagctat 
               
               
                   
               
               
                 12421 
                 gcctcacgca tccagcgccc cttctccgtg aagttcgacc cgtacacgct ggccatcgac 
               
               
                   
               
               
                 12481 
                 gtgctggaca gcccccaggc cgtgcggcgc tccctggagg gtgtccagga tgagctggac 
               
               
                   
               
               
                 12541 
                 acccttgccc atgcgctgag tgccattggc taggtgcacg gcgtccctga gggcccttcc 
               
               
                   
               
               
                 12601 
                 caacctcccc tggtcctgca ctgtcccgga gctcaggccc tggtgagggg ctgggtcccg 
               
               
                   
               
               
                 12661 
                 ggtgcccccc atgccctccc tgctgccagg ctcccactgc ccctgcacct gcttctcagc 
               
               
                   
               
               
                 12721 
                 gcaacagctg tgtgtgcccg tggtgaggtt gtgctgcctg tggtgaggtc ctgtcctggc 
               
               
                   
               
               
                 12781 
                 tcccagggtc ctgggggctg ctgcactgcc ctccgccctt ccctgacact gtctgctgcc 
               
               
                   
               
               
                 12841 
                 ccaatcaccg tcacaataaa agaaactgtg gtctctacac ctgcctggcc ccacatctgt 
               
               
                   
               
               
                 12901 
                 gccacagaga cagaccctgg gatcctcaga ctcccacacc cccaccccag cctcactcag 
               
               
                   
               
               
                 12961 
                 aggtttcgcc ctggcctcct tcctcctctg ggagatggct ggccgccctg gccaggcagc 
               
               
                   
               
               
                 13021 
                 tggcccctcc gggcctggtt tccccgctca ccctgaggcc ccgcccagct ctgagcccca 
               
               
                   
               
               
                 13081 
                 agcagctcca gaggctcggg caccctggcc gagctgcccc atctccgtgg ggtgccctcc 
               
               
                   
               
               
                 13141 
                 caaggtgggg agccacgtga cagtgggagg gcctctctca ggcctggcag ggagcagggg 
               
               
                   
               
               
                 13201 
                 tcacaaactg tgctggctgg gggtggtctc agaggtgggc ctgcaggcct aaccctccct 
               
               
                   
               
               
                 13261 
                 gctgacaggg ctcccagccc ttgagagaaa cagggatgga ggaacagctg ccctgatgcc 
               
               
                   
               
               
                 13321 
                 ctcacccacc cggagcaggc cctgcgaacc aaggggaacc tcagtgtggc ccccagcatg 
               
               
                   
               
               
                 13381 
                 tgtgctgatg gggagggtct ggctgagctg gtgcccaggc agatggtctg ggcctgtctc 
               
               
                   
               
               
                 13441 
                 cccagcgagg caggatgggg gctggatttc agactctgta agatgcccct ggcttactcg 
               
               
                   
               
               
                 13501 
                 aggggcctgg acattgccct ccagagagag cacccaacac cctccaggct tgaccggcca 
               
               
                   
               
               
                 13561 
                 gggtgtcccc ttcctacctt ggagagagca gccccagggc atcctgcagg gggtgctggg 
               
               
                   
               
               
                 13621 
                 acaccagctg gccttcaagg tctctgcctc cctccagcca ccccactaca cgctgctggg 
               
               
                   
               
               
                 13681 
                 atcctggatc tcagctcccc ggccgacaac actggcaaac tcctactcat ccacgaaggc 
               
               
                   
               
               
                 13741 
                 cctcctgggc atggtggtcc ttcccagcct ggcagtctgt tcctcacaca ccttgttagt 
               
               
                   
               
               
                 13801 
                 gcccagcccc tgaggttgca gctgggggtg tctctgaagg gctgtgagcc cccaggaagc 
               
               
                   
               
               
                 13861 
                 cctggggaag tgcctgcctt gcctcccccc ggccctgcca gcgcctggct ctgccctcct 
               
               
                   
               
               
                 13921 
                 acctgggctc cccccatcca gcctccctcc ctacacactc ctctcaagga ggcacccatg 
               
               
                   
               
               
                 13981 
                 tcctctccag ctgccgggcc tcagagcact gtggcgtcct ggggcagcca ccgcatgtcc 
               
               
                   
               
               
                 14041 
                 tgctgtggca tggctcaggg tggaaagggc ggaagggagg ggtcctgcag atagctggtg 
               
               
                   
               
               
                 14101 
                 cccactacca aacccgctcg gggcaggaga gccaaaggct gggtgtgtgc agagcggccc 
               
               
                   
               
               
                 14161 
                 cgagaggttc cgaggctgag gccagggtgg gacataggga tgcgaggggc cggggcacag 
               
               
                   
               
               
                 14221 
                 gatactccaa cctgcctgcc cccatggtct catcctcctg cttctgggac ctcctgatcc 
               
               
                   
               
               
                 14281 
                 tgcccctggt gctaagaggc aggtaggggc tgcaggcagc agggctcgga gcccatgccc 
               
               
                   
               
               
                 14341 
                 cctcaccatg ggtcaggctg gacctccagg tgcctgttct ggggagctgg gagggccgga 
               
               
                   
               
               
                 14401 
                 ggggtgtacc ccaggggctc agcccagatg acactatggg ggtgatggtg tcatgggacc 
               
               
                   
               
               
                 14461 
                 tggccaggag aggggagatg ggctcccaga agaggagtgg gggctgagag ggtgcctggg 
               
               
                   
               
               
                 14521 
                 gggccaggac ggagctgggc cagtgcacag cttcccacac ctgcccaccc ccagagtcct 
               
               
                   
               
               
                 14581 
                 gccgccaccc ccagatcaca cggaagatga ggtccgagtg gcctgctgag gacttgctgc 
               
               
                   
               
               
                 14641 
                 ttgtccccag gtccccaggt catgccctcc ttctgccacc ctggggagct gagggcctca 
               
               
                   
               
               
                 14701 
                 gctggggctg ctgtcctaag gcagggtggg aactaggcag ccagcaggga ggggacccct 
               
               
                   
               
               
                 14761 
                 ccctcactcc cactctccca cccccaccac cttggcccat ccatggcggc atcttgggcc 
               
               
                   
               
               
                 14821 
                 atccgggact ggggacaggg gtcctgggga caggggtgtg gggacagggg tcctggg 
               
            
           
         
       
     
     By “LMX1A polypeptide” (or LIM homeobox transcription factor 1-alpha) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. Q8TE12. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 9) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 mldglkmeen fqsaidtsas fssllgravs pksvcegcqr vildrfllrl ndsfwheqcv 
                   
               
               
                   
               
               
                 61 
                 qcasckeple ttcfyrdkkl yckydyeklf avkcggcfea iapnefvmra qksvyhlscf 
               
               
                   
               
               
                 121 
                 cccvcerqlq kgdefvlkeg qllckgdyek erellslvsp aasdsgksdd eeslcksahg 
               
               
                   
               
               
                 181 
                 agkgtaeegk dhkrpkrprt ilttqqrraf kasfevsskp crkvretlaa etglsvrvvq 
               
               
                   
               
               
                 241 
                 vwfqnqrakm kklarrqqqq qqdqqntqrl ssaqtngggs agmegimnpy talptpqqll 
               
               
                   
               
               
                 301 
                 aieqsvyssd pfrqgltppq mpgdhmhpyg aeplfhdlds ddtslsnlgd cflatseagp 
               
               
                   
               
               
                 361 
                 lqsrvgnpid hlysmqnsyf ts 
               
            
           
         
       
     
     By “LMX1A nucleic acid molecule” (or LIM homeobox transcription factor 1-alpha) is meant a polynucleotide encoding an LMX1A polypeptide. An exemplary LMX1A nucleic acid molecule is provided at NCBI Accession No. AH011517. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 10) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 gtataggttg gggcggagtc ggattcggga tggaaaacct ggggcaaggg atgtaggtgg 
                   
               
               
                   
               
               
                 61 
                 gggtgagggg ggcaggagaa ggagaaacgc agttgggggg cggaggccta agtacataac 
               
               
                   
               
               
                 121 
                 gtgttgactt caagtgaaat cagatcagcc agagcagttc gctgtgactg atctctcctc 
               
               
                   
               
               
                 181 
                 ccaccctaca ttctcttggc tggaccctat cctcctggct gattctggtc gccctggaca 
               
               
                   
               
               
                 241 
                 ctccctcagt tctttcccag gagtgcggtg gctgctggcg ccgagtccca gcgggcacgg 
               
               
                   
               
               
                 301 
                 acgtcagacg catcgtttct tctcctctac aggtcctccc ggcccggccc gaacatgctg 
               
               
                   
               
               
                 361 
                 gacggcctaa agatggagga gaacttccaa agcgcgatcg acacctcggc ctccttctcc 
               
               
                   
               
               
                 421 
                 tcgctgctgg gtgagtgttc aggccgtgcg tcctgggcgc actctctttc cgcttggcgc 
               
               
                   
               
               
                 481 
                 tgagctctgg agccccgctc tctgggacct ggtccgcgat agggaagcta gcgcccctct 
               
               
                   
               
               
                 541 
                 tcatacacta aattgagccc catcactatc tgtccgtcag tgcttgtggg tcgtccctac 
               
               
                   
               
               
                 601 
                 ccaaataaat ccaacaagcc gccccaggcc tcacgcactg ggcaccgaat tccccaaagc 
               
               
                   
               
               
                 661 
                 cgcgaggggc gggcgagctt gttcgtaggc gtctgagtgg caagtgatta aaaataccca 
               
               
                   
               
               
                 721 
                 gggctggatt tttaatctcg gagctgatcg acgtctcata aatgccgccc tcttctcgcg 
               
               
                   
               
               
                 781 
                 gcctagaggc aatagcatcc gagacccgag gcctggagcg cccaagttcg aggaggcttc 
               
               
                   
               
               
                 841 
                 tctcccccac caactccagc cccaatttca gccatgggca aggccgagag agacttttct 
               
               
                   
               
               
                 901 
                 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 
               
               
                   
               
               
                 961 
                 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn gggtcccggc caggtttggc 
               
               
                   
               
               
                 1021 
                 atggtctacc tgcccgggct gctcacccgc caacgtctgt tgtggctaca ggcagagcgg 
               
               
                   
               
               
                 1081 
                 tgagccccaa gtctgtctgc gagggctgtc agcgggtcat cttggacagg tttctgctgc 
               
               
                   
               
               
                 1141 
                 ggctcaacga cagcttctgg catgagcagt gcgtgcagtg cgcctcctgc aaagagcccc 
               
               
                   
               
               
                 1201 
                 tggagaccac ctgcttctac cgggacaaga agctgtactg caagtatgac tacgagaagt 
               
               
                   
               
               
                 1261 
                 aagtggccgc acccccgcag cgctccccgc gcactggcat nnnnnnnnnn nnnnnnnnnn 
               
               
                   
               
               
                 1321 
                 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 
               
               
                   
               
               
                 1381 
                 nnnnnnnnnn nnnnnnnnnn atcccagttc ttgaagttcc ttttgctgtt gacttcaggg 
               
               
                   
               
               
                 1441 
                 gagacccagg accaagccag attttactca tggtgcatgt acttcctttc tccctgctgc 
               
               
                   
               
               
                 1501 
                 caggctgttt gctgttaaat gtgggggctg cttcgaggcc atcgctccca atgagtttgt 
               
               
                   
               
               
                 1561 
                 tatgcgggcc cagaagagtg tataccacct gagctgcttc tgctgctgtg tctgcgagcg 
               
               
                   
               
               
                 1621 
                 acagcttcag aagggtgatg agtttgtcct gaaggagggg cagctgctct gcaaagggga 
               
               
                   
               
               
                 1681 
                 ctatgagaag gagcgggagc tgctcagcct ggtgagccca gcagcctcag actcaggtga 
               
               
                   
               
               
                 1741 
                 gtgccaggtg gtgggcaggg ctgcggtggg gtgggtagag tggagttggg tggctgtctg 
               
               
                   
               
               
                 1801 
                 cattgtttct tccctagatg nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 
               
               
                   
               
               
                 1861 
                 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 
               
               
                   
               
               
                 1921 
                 catacagctc caggaactgg ctttcaggga ctcacaacat tgtcttttgc ttctttcagg 
               
               
                   
               
               
                 1981 
                 taaaagtgat gatgaagaaa gtctctgcaa gtcagcccat ggggcaggga aaggaactgc 
               
               
                   
               
               
                 2041 
                 tgaggaaggc aaggaccata agcgccccaa acgtccgaga accatcttga caactcaaca 
               
               
                   
               
               
                 2101 
                 gaggcgagca ttcaaggcct catttgaagt atcctccaag ccctgcagga aggtatagga 
               
               
                   
               
               
                 2161 
                 gggagcaggg aggaaaagga gctgggcccc acttctctgt gtgcactcag acccctctgg 
               
               
                   
               
               
                 2221 
                 gatctcagtg ggcattgggg gtcacagtgg tgaggaaggc tgttcagaca gagcctgcac 
               
               
                   
               
               
                 2281 
                 aggcggctca agcctgttgg agactccaga gatcactaag ctgtggccag ggtgtgatag 
               
               
                   
               
               
                 2341 
                 actctcctga agctttcatg catgcacacc aactccaaat ggcccctgtc acacctttca 
               
               
                   
               
               
                 2401 
                 tttcatagag cacaatggga acagtaataa tgataggtgt ccattgtggt gtagacccag 
               
               
                   
               
               
                 2461 
                 atgctgtaaa gcaaagagta taaaaacaca gtggcttgca gtactctttt ttgagtctgg 
               
               
                   
               
               
                 2521 
                 ctttttccac ttggtgtggt ggtttgggga ttcattcatt cctatttcag cattccactg 
               
               
                   
               
               
                 2581 
                 tataggtgtg ccatgattgg tttgtccatg cacctgttga tgggtgtttg gggttgtttc 
               
               
                   
               
               
                 2641 
                 tagtttggga ctgtttcaaa taggactgct atggacattc atgtaaaaaa aaatacagtg 
               
               
                   
               
               
                 2701 
                 gtttaatgag acaggagttt attctcttct gtcacagtcc agaggtgagc aaggcaaggc 
               
               
                   
               
               
                 2761 
                 tggtgggtgg ctctgttatc catctcctgt gtccaagcga ctgctccagt tgtcaccatg 
               
               
                   
               
               
                 2821 
                 tttccagtca ccaggtagag aaagaggaaa tggagggcaa gcgccctgct ttttaaggat 
               
               
                   
               
               
                 2881 
                 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 
               
               
                   
               
               
                 2941 
                 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn atgcatatgc atggcttata 
               
               
                   
               
               
                 3001 
                 gctaaagcac aacaatagac taaagtctaa accacttgaa ggcctaattt ccagagcaag 
               
               
                   
               
               
                 3061 
                 agaaatccag aaacacctct tgggaatgca catgtaaatt aataattatt attttgtttc 
               
               
                   
               
               
                 3121 
                 tttacctggt gaaggacttt ctttctacct gaagggaagc aatgttctcg tgtttgtgtg 
               
               
                   
               
               
                 3181 
                 tatgctcaac attaaaaact attcagctcc taaagcagat acagtctttt ggcctcctca 
               
               
                   
               
               
                 3241 
                 agtattatat aggagatgtt ctacctccta ccctgagatg ccagtgtgtc tacatttctc 
               
               
                   
               
               
                 3301 
                 gttcaatttt tccaaggtga gagagactct ggctgcagag acagggctga gtgtccgtgt 
               
               
                   
               
               
                 3361 
                 cgtccaggtg tggttccaaa accagagagc gaaggtaacc tgcttcttac ttttatctgt 
               
               
                   
               
               
                 3421 
                 ccccatgttg ctggtttcct gaaataatca cagtaggaca nnnnnnnnnn nnnnnnnnnn 
               
               
                   
               
               
                 3481 
                 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 
               
               
                   
               
               
                 3541 
                 nnnnnnnnnn nnnnnnnnnn agccctctcc cggggaaggt gtcacttcca ggccccccct 
               
               
                   
               
               
                 3601 
                 tactttgtga acatgctgca ggccacctga cttctaatcc tatggtcctc tccttatcag 
               
               
                   
               
               
                 3661 
                 atgaagaagc tggccaggcg acagcagcag cagcagcaag atcagcagaa cacccagagg 
               
               
                   
               
               
                 3721 
                 ctgagctctg gtaagctggt gcctcctccc aggcagttct ggctggaatc caggctgttc 
               
               
                   
               
               
                 3781 
                 ctaccagagg cctcccacta cccagctctt tggatgacat atctggactc agtgaagcct 
               
               
                   
               
               
                 3841 
                 agaccacacc cactggagaa ataaggcctt caagggaaga ctgagccacg aggaacttgt 
               
               
                   
               
               
                 3901 
                 gagagggttg agggctcctg agctgcaggc ttagaactgc tgattgggga tggcactgac 
               
               
                   
               
               
                 3961 
                 cttatccaca gcgtccaggc ctggatccca ccacagcgtc agggactgct tgcagagtca 
               
               
                   
               
               
                 4021 
                 cagatacgtt cagtttctca tcttgcttag ttctccttcc aggctaattg atttaataga 
               
               
                   
               
               
                 4081 
                 agacacctcg gtgacttggc tctttccaaa ataacataaa gtagtaaaaa taatgatagt 
               
               
                   
               
               
                 4141 
                 aaaataacaa tgccttcctt tgttgaacac tcttatagat tggtgttctc atacatgctg 
               
               
                   
               
               
                 4201 
                 acttgacttt tacaacaccc attcctggag gcgagtggag aagttgttat tatccctatg 
               
               
                   
               
               
                 4261 
                 tcacagatga gcaaacaaag gctctgcaag attgaatgtg gccctagatc ggtaagggca 
               
               
                   
               
               
                 4321 
                 gggggctggg actagaactc taactgtgtt ccacaggcca tgggccttct catctctacc 
               
               
                   
               
               
                 4381 
                 cagatgtgct tttgaaaaag nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 
               
               
                   
               
               
                 4441 
                 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 
               
               
                   
               
               
                 4501 
                 cacgttgaga atgacctggc ttcttctttg ttccacagct cagacaaacg gtggtgggag 
               
               
                   
               
               
                 4561 
                 tgctgggatg gaaggaatca tgaaccccta cacggctctg cccaccccac agcagctcct 
               
               
                   
               
               
                 4621 
                 ggccatcgag cagagtgtct acagctcaga tcccttccga cagggtctca ccccacccca 
               
               
                   
               
               
                 4681 
                 gatgcctgga gaccacatgc acccttatgg taagagggac ttaagcccct cgggccctct 
               
               
                   
               
               
                 4741 
                 cataacttgt gtgggtttct cattccctcc taaacacatc taggcagttc ccagatgctc 
               
               
                   
               
               
                 4801 
                 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 
               
               
                   
               
               
                 4861 
                 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn aaatgagtca cttcttcaag 
               
               
                   
               
               
                 4921 
                 accctcatgc cagtgtttca tctccatttc aggtgccgag ccccttttcc atgacctgga 
               
               
                   
               
               
                 4981 
                 tagcgacgac acctccctca gtaacctggg tgattgtttc ctagcaacct cagaagctgg 
               
               
                   
               
               
                 5041 
                 gcctctgcag tccagagtgg gaaaccccat tgaccatctg tactccatgc agaattctta 
               
               
                   
               
               
                 5101 
                 cttcacatct tgagtcttcc cctagagttc tgtgactagg ctcccatatg gaacaaccat 
               
               
                   
               
               
                 5161 
                 attctttgag gggtcactgg ctttaggaca gggaggccag ggaagaggtg ggttggggag 
               
               
                   
               
               
                 5221 
                 ggagttttgt tggggatgct gttgtataat gatatggtgt agctcagcat ttccaaagac 
               
               
                   
               
               
                 5281 
                 tgaatacatt atggattgca tagtttaatg 
               
            
           
         
       
     
     By “FOXO1 polypeptide” (or Forkhead box protein 01) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. Q12778. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 11) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 maeapqvvei dpdfeplprp rsctwplprp efsqsnsats spapsgsaaa npdaaaglps 
                   
               
               
                   
               
               
                 61 
                 asaaaysadf msnlsllees edfpqapgsv aaavaaaaaa aatgglcgdf qgpeagclhp 
               
               
                   
               
               
                 121 
                 appqppppgp lsqhppvppa aagplagqpr kssssrrnaw gnlsyadlit kaiessaekr 
               
               
                   
               
               
                 181 
                 ltlsqiyewm vksvpyfkdk gdsnssagwk nsirhnlslh skfirvqneg tgksswwmln 
               
               
                   
               
               
                 241 
                 peggksgksp rrraasmdnn skfaksrsra akkkaslqsg qegagdspgs qfskwpaspg 
               
               
                   
               
               
                 301 
                 shsnddfdnw stfrprtssn astisgrlsp imteqddlge gdvhsmvypp saakmastlp 
               
               
                   
               
               
                 361 
                 slseisnpen menlldnlnl lssptsltvs tqsspgtmmq qtpcysfapp ntslnspspn 
               
               
                   
               
               
                 421 
                 yqkytygqss msplpqmpiq tlqdnkssyg gmsqyncapg llkelltsds pphndimtpv 
               
               
                   
               
               
                 481 
                 dpgvaqpnsr vlgqnvmmgp nsvmstygsq ashnkmmnps shthpghaqq tsavngrplp 
               
               
                   
               
               
                 541 
                 htvstmphts gmnrltqvkt pvqvplphpm qmsalggyss vsscngygrm gllhqeklps 
               
               
                   
               
               
                 601 
                 dldgmfierl dcdmesiirn dlmdgdtldf nfdnvlpnqs fphsvkttth swvsg 
               
            
           
         
       
     
     By “FOXO1 nucleic acid molecule” (or Forkhead box protein 01) is meant a polynucleotide (e.g., mRNA) encoding an FOXO1 polypeptide. An exemplary FOXO1 nucleic acid molecule is provided at NCBI Accession No. NM_002015. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 12) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 gcagccgcca cattcaacag gcagcagcgc agcgggcgcg ccgctgggga gagcaagcgg 
                   
               
               
                   
               
               
                 61 
                 cccgcggcgt ccgtccgtcc ttccgtccgc ggccctgtca gctggagcgc ggcgcaggct 
               
               
                   
               
               
                 121 
                 ctgccccggc ccggcggctc tggccggccg tccagtccgt gcggcggacc ccgaggagcc 
               
               
                   
               
               
                 181 
                 tcgatgtgga tggccccgcg aagttaagtt ctgggctcgc gcttccactc cgccgcgcct 
               
               
                   
               
               
                 241 
                 tcctcccagt ttccgtccgc tcgccgcacc ggcttcgttc ccccaaatct cggaccgtcc 
               
               
                   
               
               
                 301 
                 cttcgcgccc cctccccgtc cgcccccagt gctgcgttct ccccctcttg gctctcctgc 
               
               
                   
               
               
                 361 
                 ggctggggga ggggcggggg tcaccatggc cgaggcgcct caggtggtgg agatcgaccc 
               
               
                   
               
               
                 421 
                 ggacttcgag ccgctgcccc ggccgcgctc gtgcacctgg ccgctgccca ggccggagtt 
               
               
                   
               
               
                 481 
                 tagccagtcc aactcggcca cctccagccc ggcgccgtcg ggcagcgcgg ctgccaaccc 
               
               
                   
               
               
                 541 
                 cgacgccgcg gcgggcctgc cctcggcctc ggctgccgct gtcagcgccg acttcatgag 
               
               
                   
               
               
                 601 
                 caacctgagc ttgctggagg agagcgagga cttcccgcag gcgcccggct ccgtggcggc 
               
               
                   
               
               
                 661 
                 ggcggtggcg gcggcggccg ccgcggccgc caccgggggg ctgtgcgggg acttccaggg 
               
               
                   
               
               
                 721 
                 cccggaggcg ggctgcctgc acccagcgcc accgcagccc ccgccgcccg ggccgctgtc 
               
               
                   
               
               
                 781 
                 gcagcacccg ccggtgcccc ccgccgccgc tgggccgctc gcggggcagc cgcgcaagag 
               
               
                   
               
               
                 841 
                 cagctcgtcc cgccgcaacg cgtggggcaa cctgtcctac gccgacctca tcaccaaggc 
               
               
                   
               
               
                 901 
                 catcgagagc tcggcggaga agcggctcac gctgtcgcag atctacgagt ggatggtcaa 
               
               
                   
               
               
                 961 
                 gagcgtgccc tacttcaagg ataagggtga cagcaacagc tcggcgggct ggaagaattc 
               
               
                   
               
               
                 1021 
                 aattcgtcat aatctgtccc tacacagcaa gttcattcgt gtgcagaatg aaggaactgg 
               
               
                   
               
               
                 1081 
                 aaaaagttct tggtggatgc tcaatccaga gggtggcaag agcgggaaat ctcctaggag 
               
               
                   
               
               
                 1141 
                 aagagctgca tccatggaca acaacagtaa atttgctaag agccgaagcc gagctgccaa 
               
               
                   
               
               
                 1201 
                 gaagaaagca tctctccagt ctggccagga gggtgctggg gacagccctg gatcacagtt 
               
               
                   
               
               
                 1261 
                 ttccaaatgg cctgcaagcc ctggctctca cagcaatgat gactttgata actggagtac 
               
               
                   
               
               
                 1321 
                 atttcgccct cgaactagct caaatgctag tactattagt gggagactct cacccattat 
               
               
                   
               
               
                 1381 
                 gaccgaacag gatgatcttg gagaagggga tgtgcattct atggtgtacc cgccatctgc 
               
               
                   
               
               
                 1441 
                 cgcaaagatg gcctctactt tacccagtct gtctgagata agcaatcccg aaaacatgga 
               
               
                   
               
               
                 1501 
                 aaatcttttg gataatctca accttctctc atcaccaaca tcattaactg tttcgaccca 
               
               
                   
               
               
                 1561 
                 gtcctcacct ggcaccatga tgcagcagac gccgtgctac tcgtttgcgc caccaaacac 
               
               
                   
               
               
                 1621 
                 cagtttgaat tcacccagcc caaactacca aaaatataca tatggccaat ccagcatgag 
               
               
                   
               
               
                 1681 
                 ccctttgccc cagatgccta tacaaacact tcaggacaat aagtcgagtt atggaggtat 
               
               
                   
               
               
                 1741 
                 gagtcagtat aactgtgcgc ctggactctt gaaggagttg ctgacttctg actctcctcc 
               
               
                   
               
               
                 1801 
                 ccataatgac attatgacac cagttgatcc tggggtagcc cagcccaaca gccgggttct 
               
               
                   
               
               
                 1861 
                 gggccagaac gtcatgatgg gccctaattc ggtcatgtca acctatggca gccaggcatc 
               
               
                   
               
               
                 1921 
                 tcataacaaa atgatgaatc ccagctccca tacccaccct ggacatgctc agcagacatc 
               
               
                   
               
               
                 1981 
                 tgcagttaac gggcgtcccc tgccccacac ggtaagcacc atgccccaca cctcgggtat 
               
               
                   
               
               
                 2041 
                 gaaccgcctg acccaagtga agacacctgt acaagtgcct ctgccccacc ccatgcagat 
               
               
                   
               
               
                 2101 
                 gagtgccctg gggggctact cctccgtgag cagctgcaat ggctatggca gaatgggcct 
               
               
                   
               
               
                 2161 
                 tctccaccag gagaagctcc caagtgactt ggatggcatg ttcattgagc gcttagactg 
               
               
                   
               
               
                 2221 
                 tgacatggaa tccatcattc ggaatgacct catggatgga gatacattgg attttaactt 
               
               
                   
               
               
                 2281 
                 tgacaatgtg ttgcccaacc aaagcttccc acacagtgtc aagacaacga cacatagctg 
               
               
                   
               
               
                 2341 
                 ggtgtcaggc tgagggttag tgagcaggtt acacttaaaa gtacttcaga ttgtctgaca 
               
               
                   
               
               
                 2401 
                 gcaggaactg agagaagcag tccaaagatg tctttcacca actccctttt agttttcttg 
               
               
                   
               
               
                 2461 
                 gttaaaaaaa aaaacaaaaa aaaaaaccct ccttttttcc tttcgtcaga cttggcagca 
               
               
                   
               
               
                 2521 
                 aagacatttt tcctgtacag gatgtttgcc caatgtgtgc aggttatgtg ctgctgtaga 
               
               
                   
               
               
                 2581 
                 taaggactgt gccattggaa atttcattac aatgaagtgc caaactcact acaccatata 
               
               
                   
               
               
                 2641 
                 attgcagaaa agattttcag atcctggtgt gctttcaagt tttgtatata agcagtagat 
               
               
                   
               
               
                 2701 
                 acagattgta tttgtgtgtg tttttggttt ttctaaatat ccaattggtc caaggaaagt 
               
               
                   
               
               
                 2761 
                 ttatactctt tttgtaatac tgtgatgggc ctcatgtctt gataagttaa acttttgttt 
               
               
                   
               
               
                 2821 
                 gtactacctg ttttctgcgg aactgacgga tcacaaagaa ctgaatctcc attctgcatc 
               
               
                   
               
               
                 2881 
                 tccattgaac agccttggac ctgttcacgt tgccacagaa ttcacatgag aaccaagtag 
               
               
                   
               
               
                 2941 
                 cctgttatca atctgctaaa ttaatggact tgttaaactt ttggaaaaaa aaagattaaa 
               
               
                   
               
               
                 3001 
                 tgccagcttt gtacaggtct tttctatttt tttttgttta ttttgttatt tgcaaatttg 
               
               
                   
               
               
                 3061 
                 tacaaacatt taaatggttc taatttccag ataaatgatt tttgatgtta ttgttgggac 
               
               
                   
               
               
                 3121 
                 ttaagaacat ttttggaata gatattgaac tgtaataatg ttttcttaaa actagagtct 
               
               
                   
               
               
                 3181 
                 actttgttac atagtcagct tgtaaatttt gtggaaccac aggtatttgg ggcagcattc 
               
               
                   
               
               
                 3241 
                 ataattttca ttttgtattc taactggatt agtactaatt ttatacatgc ttaactggtt 
               
               
                   
               
               
                 3301 
                 tgtacacttt gggatgctac ttagtgatgt ttctgactaa tcttaaatca ttgtaattag 
               
               
                   
               
               
                 3361 
                 tacttgcata ttcaacgttt caggccctgg ttgggcagga aagtgatgta tagttatgga 
               
               
                   
               
               
                 3421 
                 cactttgcgt ttcttattta ggataactta atatgttttt atgtatgtat tttaaagaaa 
               
               
                   
               
               
                 3481 
                 tttcatctgc ttctactgaa ctatgcgtac tgcatagcat caagtcttct ctagagacct 
               
               
                   
               
               
                 3541 
                 ctgtagtcct gggaggcctc ataatgtttg tagatcagaa aagggagatc tgcatctaaa 
               
               
                   
               
               
                 3601 
                 gcaatggtcc tttgtcaaac gagggatttt gatccacttc accattttga gttgagcttt 
               
               
                   
               
               
                 3661 
                 agcaaaagtt tcccctcata attctttgct cttgtttcag tccaggtgga ggttggtttt 
               
               
                   
               
               
                 3721 
                 gtagttctgc cttgaggaat tatgtcaaca ctcatacttc atctcattct cccttctgcc 
               
               
                   
               
               
                 3781 
                 ctgcagatta gattacttag cacactgtgg aagtttaagt ggaaggaggg aatttaaaaa 
               
               
                   
               
               
                 3841 
                 tgggacttga gtggtttgta gaatttgtgt tcataagttc agatgggtag caaatggaat 
               
               
                   
               
               
                 3901 
                 agaacttact taaaaattgg ggagatttat ttgaaaacca gctgtaagtt gtgcattgag 
               
               
                   
               
               
                 3961 
                 attatgttaa aagccttggc ttaagaattt gaaaatttct ttagcctgta gcaacctaaa 
               
               
                   
               
               
                 4021 
                 ctgtaattcc tatcattatg ttttattact ttccaattac ctgtaactga cagaccaaat 
               
               
                   
               
               
                 4081 
                 taattggctt tgtgtcctat ttagtccatc agtattttca agtcatgtgg aaagcccaaa 
               
               
                   
               
               
                 4141 
                 gtcatcacaa tgaagagaac aggtgcacag cactgttcct cttgtgttct tgagaaggat 
               
               
                   
               
               
                 4201 
                 ctaatttttc tgtatatagc ccacatcaca cttgctttgt cttgtatgtt aattgcatct 
               
               
                   
               
               
                 4261 
                 tcattggctt ggtatttcct aaatgtttaa caagaacaca agtgttcctg ataagatttc 
               
               
                   
               
               
                 4321 
                 ctacagtaag ccagctctat tgtaagcttc ccactgtgat gatcattttt ttgaagattc 
               
               
                   
               
               
                 4381 
                 attgaacagc caccactcta tcatcctcat tttggggcag tccaagacat agctggtttt 
               
               
                   
               
               
                 4441 
                 agaaacccaa gttcctctaa gcacagcctc ccgggtatgt aactgaactt ggtgccaaag 
               
               
                   
               
               
                 4501 
                 tacttgtgta ctaatttcta ttactacgta ctgtcacttt cctcccgtgc cattactgca 
               
               
                   
               
               
                 4561 
                 tcataataca aggaacctca gagcccccat ttgttcatta aagaggcaac tacagccaaa 
               
               
                   
               
               
                 4621 
                 atcactgtta aaatcttact acttcatgga gtagctctta ggaaaatata tcttcctcct 
               
               
                   
               
               
                 4681 
                 gagtctgggt aattatacct ctcccaagcc cccattgtgt gttgaaatcc tgtcatgaat 
               
               
                   
               
               
                 4741 
                 ccttggtagc tctctgagaa cagtgaagtc cagggaaagg catctggtct gtctggaaag 
               
               
                   
               
               
                 4801 
                 caaacattat gtggcctctg gtagtttttt tcctgtaaga atactgactt tctggagtaa 
               
               
                   
               
               
                 4861 
                 tgagtatata tcagttattg tacatgattg ctttgtgaaa tgtgcaaatg atatcaccta 
               
               
                   
               
               
                 4921 
                 tgcagccttg tttgatttat tttctctggt ttgtactgtt attaaaagca tattgtatta 
               
               
                   
               
               
                 4981 
                 tagagctatt cagatatttt aaatataaag atgtattgtt tccgtaatat agacgtatgg 
               
               
                   
               
               
                 5041 
                 aatatattta ggtaatagat gtattacttg gaaagttctg ctttgacaaa ctgacaaagt 
               
               
                   
               
               
                 5101 
                 ctaaatgagc acatgtatcc cagtgagcag taaatcaatg gaacatccca agaagaggat 
               
               
                   
               
               
                 5161 
                 aaggatgctt aaaatggaaa tcattctcca acgatataca aattggactt gttcaactgc 
               
               
                   
               
               
                 5221 
                 tggatatatg ctaccaataa ccccagcccc aacttaaaat tcttacattc aagctcctaa 
               
               
                   
               
               
                 5281 
                 gagttcttaa tttataacta attttaaaag agaagtttct tttctggttt tagtttggga 
               
               
                   
               
               
                 5341 
                 ataatcattc attaaaaaaa atgtattgtg gtttatgcga acagaccaac ctggcattac 
               
               
                   
               
               
                 5401 
                 agttggcctc tccttgaggt gggcacagcc tggcagtgtg gccaggggtg gccatgtaag 
               
               
                   
               
               
                 5461 
                 tcccatcagg acgtagtcat gcctcctgca tttcgctacc cgagtttagt aacagtgcag 
               
               
                   
               
               
                 5521 
                 attccacgtt cttgttccga tactctgaga agtgcctgat gttgatgtac ttacagacac 
               
               
                   
               
               
                 5581 
                 aagaacaatc tttgctataa ttgtataaag ccataaatgt acataaatta tgtttaaatg 
               
               
                   
               
               
                 5641 
                 gcttggtgtc tttcttttct aattatgcag aataagctct ttattaggaa ttttttgtga 
               
               
                   
               
               
                 5701 
                 agctattaaa tacttgagtt aagtcttgtc agccacaa 
               
            
           
         
       
     
     By “FOXA2 polypeptide” (or Forkhead box protein A2) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. Q9Y261. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 13) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 mlgavkmegh epsdwssyya epegyssysn mnaglgmngm ntymsmsaaa mgsgsgnmsa 
                   
               
               
                   
               
               
                 61 
                 gsmnmssyvg agmspslagm spgagamagm ggsagaagva gmgphlspsl splggqaaga 
               
               
                   
               
               
                 121 
                 mgglapyanm nsmspmygqa glsrardpkt yrrsythakp pysyislitm aiqqspnkml 
               
               
                   
               
               
                 181 
                 tlseiyqwim dlfpfyrqnq qrwqnsirhs lsfndcflkv prspdkpgkg sfwtlhpdsg 
               
               
                   
               
               
                 241 
                 nmfengcylr rqkrfkcekq lalkeaagaa gsgkkaaaga qasqaqlgea agpasetpag 
               
               
                   
               
               
                 301 
                 tesphssasp cqehkrgglg elkgtpaaal sppepapspg qqqqaaahll gpphhpglpp 
               
               
                   
               
               
                 361 
                 eahlkpehhy afnhpfsinn lmsseqqhhh shhhhqphkm dlkayeqvmh ypgygspmpg 
               
               
                   
               
               
                 421 
                 slamgpvtnk tgldasplaa dtsyyqgvys rpimnss 
               
            
           
         
       
     
     By “FOXA2 nucleic acid molecule” (or Forkhead box protein A2) is meant a polynucleotide (e.g., mRNA) encoding an FOXA2 polypeptide. An exemplary FOXA2 nucleic acid molecule is provided at NCBI Accession No. NM_021784. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 14) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 cccgcccact tccaactacc gcctccggcc tgcccaggga gagagaggga gtggagccca 
                   
               
               
                   
               
               
                 61 
                 gggagaggga gcgcgagaga gggagggagg aggggacggt gctttggctg actttttttt 
               
               
                   
               
               
                 121 
                 aaaagagggt gggggtgggg ggtgattgct ggtcgtttgt tgtggctgtt aaattttaaa 
               
               
                   
               
               
                 181 
                 ctgccatgca ctcggcttcc agtatgctgg gagcggtgaa gatggaaggg cacgagccgt 
               
               
                   
               
               
                 241 
                 ccgactggag cagctactat gcagagcccg agggctactc ctccgtgagc aacatgaacg 
               
               
                   
               
               
                 301 
                 ccggcctggg gatgaacggc atgaacacgt acatgagcat gtcggcggcc gccatgggca 
               
               
                   
               
               
                 361 
                 gcggctcggg caacatgagc gcgggctcca tgaacatgtc gtcgtacgtg ggcgctggca 
               
               
                   
               
               
                 421 
                 tgagcccgtc cctggcgggg atgtcccccg gcgcgggcgc catggcgggc atgggcggct 
               
               
                   
               
               
                 481 
                 cggccggggc ggccggcgtg gcgggcatgg ggccgcactt gagtcccagc ctgagcccgc 
               
               
                   
               
               
                 541 
                 tcggggggca ggcggccggg gccatgggcg gcctggcccc ctacgccaac atgaactcca 
               
               
                   
               
               
                 601 
                 tgagccccat gtacgggcag gcgggcctga gccgcgcccg cgaccccaag acctacaggc 
               
               
                   
               
               
                 661 
                 gcagctacac gcacgcaaag ccgccctact cgtacatctc gctcatcacc atggccatcc 
               
               
                   
               
               
                 721 
                 agcagagccc caacaagatg ctgacgctga gcgagatcta ccagtggatc atggacctct 
               
               
                   
               
               
                 781 
                 tccccttcta ccggcagaac cagcagcgct ggcagaactc catccgccac tcgctctcct 
               
               
                   
               
               
                 841 
                 tcaacgactg tttcctgaag gtgccccgct cgcccgacaa gcccggcaag ggctccttct 
               
               
                   
               
               
                 901 
                 ggaccctgca ccctgactcg ggcaacatgt tcgagaacgg ctgctacctg cgccgccaga 
               
               
                   
               
               
                 961 
                 agcgcttcaa gtgcgagaag cagctggcgc tgaaggaggc cgcaggcgcc gccggcagcg 
               
               
                   
               
               
                 1021 
                 gcaagaaggc ggccgccgga gcccaggcct cacaggctca actcggggag gccgccgggc 
               
               
                   
               
               
                 1081 
                 cggcctccga gactccggcg ggcaccgagt cgcctcactc gagcgcctcc ccgtgccagg 
               
               
                   
               
               
                 1141 
                 agcacaagcg agggggcctg ggagagctga aggggacgcc ggctgcggcg ctgagccccc 
               
               
                   
               
               
                 1201 
                 cagagccggc gccctctccc gggcagcagc agcaggccgc ggcccacctg ctgggcccgc 
               
               
                   
               
               
                 1261 
                 cccaccaccc gggcctgccg cctgaggccc acctgaagcc ggaacaccac tacgccttca 
               
               
                   
               
               
                 1321 
                 accacccgtt ctccatcaac aacctcatgt cctcggagca gcagcaccac cacagccacc 
               
               
                   
               
               
                 1381 
                 accaccacca accccacaaa atggacctca aggcctacga acaggtgatg cactaccccg 
               
               
                   
               
               
                 1441 
                 gctacggttc ccccatgcct ggcagcttgg ccatgggccc ggtcacgaac aaaacgggcc 
               
               
                   
               
               
                 1501 
                 tggacgcctc gcccctggcc gcagatacct cctactacca gggggtgtac tcccggccca 
               
               
                   
               
               
                 1561 
                 ttatgaactc ctcttaagaa gacgacggct tcaggcccgg ctaactctgg caccccggat 
               
               
                   
               
               
                 1621 
                 cgaggacaag tgagagagca agtgggggtc gagactttgg ggagacggtg ttgcagagac 
               
               
                   
               
               
                 1681 
                 gcaagggaga agaaatccat aacaccccca ccccaacacc cccaagacag cagtcttctt 
               
               
                   
               
               
                 1741 
                 cacccgctgc agccgttccg tcccaaacag agggccacac agatacccca cgttctatat 
               
               
                   
               
               
                 1801 
                 aaggaggaaa acgggaaaga atataaagtt aaaaaaaagc ctccggtttc cactactgtg 
               
               
                   
               
               
                 1861 
                 tagactcctg cttcttcaag cacctgcaga ttctgatttt tttgttgttg ttgttctcct 
               
               
                   
               
               
                 1921 
                 ccattgctgt tgttgcaggg aagtcttact taaaaaaaaa aaaaaatttt gtgagtgact 
               
               
                   
               
               
                 1981 
                 cggtgtaaaa ccatgtagtt ttaacagaac cagagggttg tactattgtt taaaaacagg 
               
               
                   
               
               
                 2041 
                 aaaaaaaata atgtaagggt ctgttgtaaa tgaccaagaa aaagaaaaaa aaagcattcc 
               
               
                   
               
               
                 2101 
                 caatcttgac acggtgaaat ccaggtctcg ggtccgatta atttatggtt tctgcgtgct 
               
               
                   
               
               
                 2161 
                 ttatttatgg cttataaatg tgtattctgg ctgcaagggc cagagttcca caaatctata 
               
               
                   
               
               
                 2221 
                 ttaaagtgtt atacccggtt ttatcccttg aatcttttct tccagatttt tcttttcttt 
               
               
                   
               
               
                 2281 
                 acttggctta caaaatatac aggcttggaa attatttcaa gaaggaggga gggataccct 
               
               
                   
               
               
                 2341 
                 gtctggttgc aggttgtatt ttattttggc ccagggagtg ttgctgtttt cccaacattt 
               
               
                   
               
               
                 2401 
                 tattaataaa attttcagac ataaaaaa 
               
            
           
         
       
     
     By “FOXO4 polypeptide” (or Forkhead box protein 04) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. P98177. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 15) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 mdpgnensat eaaaiidldp dfepqsrprs ctwplprpei anqpseppev epdlgekvht 
                   
               
               
                   
               
               
                 61 
                 egrsepillp srlpepaggp qpgilgavtg prkggsrrna wgnqsyaeli sqaiesapek 
               
               
                   
               
               
                 121 
                 rltlaqiyew mvrtvpyfkd kgdsnssagw knsirhnlsl hskfikvhne atgksswwml 
               
               
                   
               
               
                 181 
                 npeggksgka prrraasmds sskllrgrsk apkkkpsvlp appegatpts pvghfakwsg 
               
               
                   
               
               
                 241 
                 spcsrnreea dmwttfrprs ssnassystr lsplrpesev laeeipasvs syaggvpptl 
               
               
                   
               
               
                 301 
                 neglelldgl nitsshslls rsglsgfslq hpgvtgplht yssslfspae gplsagegcf 
               
               
                   
               
               
                 361 
                 sssqaleall tsdtppppad vlmtqvdpil sqaptllllg glpsssklat gvglcpkple 
               
               
                   
               
               
                 421 
                 apgpsslvpt lsmiapppvm asapipkalg tpvltpptea asqdrmpqdl dldmymenle 
               
               
                   
               
               
                 481 
                 cdmdniisdl mdegegldfn fepdp 
               
            
           
         
       
     
     By “FOXO4 nucleic acid molecule” (or Forkhead box protein 04) is meant a polynucleotide (e.g., mRNA) encoding an FOXO4 polypeptide. An exemplary FOXO4 nucleic acid molecule is provided at NCBI Accession No. NM_005938. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 16) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 aaaaggggga gggaactgcg gctaaggaga cgttcggtga tgggagcgca atatatgagg 
                   
               
               
                   
               
               
                 61 
                 ggatacagtg cctcaggttt aaaagagcag gaagctgagt gagaggttgc agaaaaagtg 
               
               
                   
               
               
                 121 
                 tcttcgctcg gcagaggtta caggtggcat ctcagaaaga gctttgaggc tacaggctgt 
               
               
                   
               
               
                 181 
                 agtcgggaag gggatcggag aactgtgtga agggacagct tagggactag cgtcctggga 
               
               
                   
               
               
                 241 
                 ctagggggaa gttcgcgact ttctgaagac tggcaggaat gtgcctcctg gccctcgatg 
               
               
                   
               
               
                 301 
                 cttcccccct gaggggaggc atcgtgaggg actgtggcag gcttcactga acgctgagcc 
               
               
                   
               
               
                 361 
                 ggggaggtcc aactccacgt atggatccgg ggaatgagaa ttcagccaca gaggctgccg 
               
               
                   
               
               
                 421 
                 cgatcataga cctagatccc gacttcgaac cccagagccg tccccgctcc tgcacctggc 
               
               
                   
               
               
                 481 
                 cccttccccg accagagatc gctaaccagc cgtccgagcc gcccgaggtg gagccagatc 
               
               
                   
               
               
                 541 
                 tgggggaaaa ggtacacacg gaggggcgct cagagccgat cctgttgccc tctcggctcc 
               
               
                   
               
               
                 601 
                 cagagccggc cgggggcccc cagcccggaa tcctgggggc tgtaacaggt cctcggaagg 
               
               
                   
               
               
                 661 
                 gaggctcccg ccggaatgcc tggggaaatc agtcatatgc agaactcatc agccaggcca 
               
               
                   
               
               
                 721 
                 ttgaaagcgc cccggagaag cgactgacac ttgcccagat ctacgagtgg atggtccgta 
               
               
                   
               
               
                 781 
                 ctgtacccta cttcaaggac aagggtgaca gcaacagctc agcaggatgg aagaactcga 
               
               
                   
               
               
                 841 
                 tccgccacaa cctgtccctg cacagcaagt tcatcaaggt tcacaacgag gccaccggca 
               
               
                   
               
               
                 901 
                 aaagctcttg gtggatgctg aaccctgagg gaggcaagag cggcaaagcc ccccgccgcc 
               
               
                   
               
               
                 961 
                 gggccgcctc catggatagc agcagcaagc tgctccgggg ccgcagtaaa gcccccaaga 
               
               
                   
               
               
                 1021 
                 agaaaccatc tgtgctgcca gctccacccg aaggtgccac tccaacgagc cctgtcggcc 
               
               
                   
               
               
                 1081 
                 actttgccaa gtggtcaggc agcccttgct ctcgaaaccg tgaagaagcc gatatgtgga 
               
               
                   
               
               
                 1141 
                 ccaccttccg tccacgaagc agttcaaatg ccagcagtgt cagcacccgg ctgtccccct 
               
               
                   
               
               
                 1201 
                 tgaggccaga gtctgaggtg ctggcggagg aaataccagc ttcagtcagc agttatgcag 
               
               
                   
               
               
                 1261 
                 ggggtgtccc tcccaccctc aatgaaggtc tagagctgtt agatgggctc aatctcacct 
               
               
                   
               
               
                 1321 
                 cttcccattc cctgctatct cggagtggtc tctctggctt ctctttgcag catcctgggg 
               
               
                   
               
               
                 1381 
                 ttaccggccc cttacacacc tacagcagct cccttttcag cccagcagag gggcccctgt 
               
               
                   
               
               
                 1441 
                 cagcaggaga agggtgcttc tccagctccc aggctctgga ggccctgctc acctctgata 
               
               
                   
               
               
                 1501 
                 cgccaccacc ccctgctgac gtcctcatga cccaggtaga tcccattctg tcccaggctc 
               
               
                   
               
               
                 1561 
                 cgactcttct gttgctgggg gggcttcctt cctccagtaa gctggccacg ggcgtcggcc 
               
               
                   
               
               
                 1621 
                 tgtgtcccaa gcccctagag gctccaggcc ccagcagtct ggttcccacc ctttctatga 
               
               
                   
               
               
                 1681 
                 tagcaccacc tccagtcatg gcaagtgccc ccatccccaa ggctctgggg actcctgtgc 
               
               
                   
               
               
                 1741 
                 tcacaccccc tactgaagct gcaagccaag acagaatgcc tcaggatcta gatcttgata 
               
               
                   
               
               
                 1801 
                 tgtatatgga gaacctggag tgtgacatgg ataacatcat cagtgacctc atggatgagg 
               
               
                   
               
               
                 1861 
                 gcgagggact ggacttcaac tttgagccag atccctgagt catgcctgga agctttgtcc 
               
               
                   
               
               
                 1921 
                 cctgcttcag atgtggagcc aggcgtgttc atatctactc tttacccttg agccctcccc 
               
               
                   
               
               
                 1981 
                 aggaatttgg gaccctgctt tagagctagg gtggggtctg gtcacacaca ggtgttgaag 
               
               
                   
               
               
                 2041 
                 aaattataaa gataaagctg ccccatctgg ggacgatatg gggagggaga tgggagggga 
               
               
                   
               
               
                 2101 
                 aaggggagag ggtttttctc actgtgccaa ttagggggta aggccccctc tcaggagcca 
               
               
                   
               
               
                 2161 
                 tcatcggctt tccccattcc tacccactta ggctttgtag caagatgagc aatgctgttg 
               
               
                   
               
               
                 2221 
                 gaaatgtgaa gtcaccagtg gccttacccc tgcctttggg agcaggattt ttttgtagag 
               
               
                   
               
               
                 2281 
                 agtcttatct gagctgagcc aggctagctg gagcctggga tttctatgca gtggcccctt 
               
               
                   
               
               
                 2341 
                 aggccagtga tgtgcggtgg gtgggctgtt taggggatct ggaagggcca aggtctgagc 
               
               
                   
               
               
                 2401 
                 actggagtgg ctcgccaggc caaatcaccc ttagaaggct gcagataaca gaaaggcttt 
               
               
                   
               
               
                 2461 
                 ttataaactt ttaaagaaat ataaacacaa atatagagat tttttaacca tggcagggtg 
               
               
                   
               
               
                 2521 
                 ctagtggtgg gcagaatgct tttttttctt tctgaaggct ttgtgatagt gacatgatac 
               
               
                   
               
               
                 2581 
                 aaacactaca gacaataaat attaggagac acagggaagt ggggagaggt ggggagtaat 
               
               
                   
               
               
                 2641 
                 agtaaacaca gggaagagct cccctacgga ccaggtatag agaaaggtct atgcagaaat 
               
               
                   
               
               
                 2701 
                 aggttagagt ttccctaaca aaaaagctaa cccaggtccc ctcattcctt caacttgtgc 
               
               
                   
               
               
                 2761 
                 ctgggagtgt gtggtgttag ggtgcagcca cactcttcta tgacccagca tgggttagtg 
               
               
                   
               
               
                 2821 
                 ctatggtggg agagtacatt gaaggcctgg aattagcttg gggccaggga agggactggg 
               
               
                   
               
               
                 2881 
                 aggggagaga agagaaggag ggaaggattt aggatggtaa agttaggtac agagacctcc 
               
               
                   
               
               
                 2941 
                 ctgttcaagg cccctgacag ctgtccctgc ccttcttccc cttccctgac tgcaggggtt 
               
               
                   
               
               
                 3001 
                 atgtggaagt gtgtgtggca gcaggcagcg gggaggggag gaacagggaa gggggagctg 
               
               
                   
               
               
                 3061 
                 gggagcttgg ctgagggtct gggaaatgag cagggatggg gggggatgtg gatcaggttt 
               
               
                   
               
               
                 3121 
                 actagcacct gccagggagg ccatctgggg ctccttctcc accccagccc ccaaagcagc 
               
               
                   
               
               
                 3181 
                 ccttccccca gtgccctttg catcgtcccc tcccccaccc ctgctgtggg ttcccatcat 
               
               
                   
               
               
                 3241 
                 ttcctgtgtc agcgcctggc ctacccagat tgtatcatgt gctagattgg agtggggaag 
               
               
                   
               
               
                 3301 
                 tgtgtcaaat caataaatga ataaattcaa taaatgccta taaccagcaa aaaaaaaaaa 
               
               
                   
               
               
                 3361 
                 aaaaa 
               
            
           
         
       
     
     By “CNP polypeptide” (or 2′,3′-cyclic-nucleotide 3′-phosphodiesterase) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. P09543. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 17) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 mnrgfsrksh tflpkiffrk msssgakdkp elqfpflqde dtvatlleck tlfilrglpg 
                   
               
               
                   
               
               
                 61 
                 sgkstlarvi vdkyrdgtkm vsadaykitp gargafseey krldedlaay crrrdirilv 
               
               
                   
               
               
                 121 
                 lddtnherer leqlfemadq yqyqvvlvep ktawrldcaq lkeknqwqls addlkklkpg 
               
               
                   
               
               
                 181 
                 lekdflplyf gwfltkksse tlrkagqvfl eelgnhkafk kelrqfvpgd eprekmdlvt 
               
               
                   
               
               
                 241 
                 yfgkrppgvl hcttkfcdyg kapgaeeyaq qdvlkksysk aftltisalf vtpkttgary 
               
               
                   
               
               
                 301 
                 elseqqlqlw psdvdklspt dnlprgsrah itlgcaadve avqtgldlle ilrqekggsr 
               
               
                   
               
               
                 361 
                 geevgelsrg klyslgngrw mltlaknmev raiftgyygk gkpvptqgsr kggalqscti 
               
               
                   
               
               
                 421 
                 i 
               
            
           
         
       
     
     By “CNP nucleic acid molecule” (or 2′,3′-cyclic-nucleotide 3′-phosphodiesterase) is meant a polynucleotide (e.g., mRNA) encoding an CNP polypeptide. An exemplary CNP nucleic acid molecule is provided at NCBI Accession No. BC011046. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 18) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 ctccgcgcag gcgggcggcc ccggagcgct ggtgccggca gaggcggcga cggtggcgcc 
                   
               
               
                   
               
               
                 61 
                 cctcctcatc atgaggcttc tcccgaaaaa gccacacatt cctgcccaag atcttcttcc 
               
               
                   
               
               
                 121 
                 gcaagatgtc atcctcaggg gccaaggaca agcctgagct gcagtttccc ttccttcagg 
               
               
                   
               
               
                 181 
                 atgaggacac agtggccacg ctgctagagt gcaagacgct cttcatcttg cgcggcctgc 
               
               
                   
               
               
                 241 
                 caggaagcgg caagtccacg ctggcacggg tcatcgtgga caagtaccgt gatggcacca 
               
               
                   
               
               
                 301 
                 agatggtgtc ggctgacgct tacaagatca cccccggcgc tcgaggagcc ttctccgagg 
               
               
                   
               
               
                 361 
                 agtacaagcg gctcgatgag gacctggctg cctactgccg ccgccgggac atcagaattc 
               
               
                   
               
               
                 421 
                 ttgtgcttga tgacaccaac cacgaacggg aacggctgga gcagctcttt gaaatggccg 
               
               
                   
               
               
                 481 
                 accagtacca gtaccaggtg gtgctggtgg agcccaagac ggcgtggcgg ctggactgtg 
               
               
                   
               
               
                 541 
                 cccagctcaa ggagaagaac cagtggcagc tgtcggctga tgacctgaag aagctgaagc 
               
               
                   
               
               
                 601 
                 ctgggctgga gaaggacttc ctgccgctct acttcggctg gttcctgacc aagaagagct 
               
               
                   
               
               
                 661 
                 ctgagaccct ccgcaaagcc ggccaggtct tcctggaaga gctggggaac cacaaggcct 
               
               
                   
               
               
                 721 
                 tcaagaagga gctgcgacaa ttcgtccctg gggatgagcc cagggagaag atggacttgg 
               
               
                   
               
               
                 781 
                 tcacctactt tggaaagaga cccccaggcg tgctgcattg cacaaccaag ttttgtgact 
               
               
                   
               
               
                 841 
                 acgggaaggc tcccggggca gaggagtacg ctcaacaaga tgtgttaaag aaatcttact 
               
               
                   
               
               
                 901 
                 ccaaggcctt cacgctgacc atctctgccc tctttgtgac acccaagacg actggggccc 
               
               
                   
               
               
                 961 
                 gggtggagtt aagcgagcag caactgcagt tgtggccgag tgatgtggac aagctgtcac 
               
               
                   
               
               
                 1021 
                 ccactgacaa cctgccgcgg gggagccgcg cccacatcac cctcggctgt gcagctgacg 
               
               
                   
               
               
                 1081 
                 tagaggccgt gcagacgggc cttgacctct tagagattct gcggcaggag aaggggggca 
               
               
                   
               
               
                 1141 
                 gccgaggcga ggaggtgggc gagctaagcc ggggcaagct ctattccttg ggcaatgggc 
               
               
                   
               
               
                 1201 
                 gctggatgct gaccctggcc aagaacatgg aggtcagggc catcttcacg gggtactacg 
               
               
                   
               
               
                 1261 
                 ggaaaggcaa acctgtgccc acgcaaggta gccggaaggg gggcgccttg cagtcctgca 
               
               
                   
               
               
                 1321 
                 ccatcatatg agtgttctca ccaccactta tgcccctaga agggaagggg agagggaaac 
               
               
                   
               
               
                 1381 
                 gtgccctctg tttgatcctt gttttgtgac attttttttt tttttttttt tactcaaagt 
               
               
                   
               
               
                 1441 
                 taacctacct gtaacttttt aaaaacttgt aaaataactg accctccctt cctgtccgcc 
               
               
                   
               
               
                 1501 
                 ctcttcccct ctaatgctca cgctcccaac acaaggtggg cagggaggca ccattcagga 
               
               
                   
               
               
                 1561 
                 acctggacca aagctgacga ggctgggcca agccagggat ggggccacag ccagaacccc 
               
               
                   
               
               
                 1621 
                 gagccctact tccaggttct ggttagctca gccccagccc agcccagctg ctctgcccag 
               
               
                   
               
               
                 1681 
                 agctgggtga gtggggagac acctcagagc cccgcaaaac ccactgaccg gaggcaaaag 
               
               
                   
               
               
                 1741 
                 gcagtggggc tgggggtagt tttccatggt cacagagaac tagtggtggc tctgagaagg 
               
               
                   
               
               
                 1801 
                 ggaggacctc tgggctttga ttccatctcc ttgtcttttt tctttgtttt tagagacagg 
               
               
                   
               
               
                 1861 
                 gtcctgctat ttcccaagct ggagtgcagt ggtgcgatca tggctcactg cagcctcgaa 
               
               
                   
               
               
                 1921 
                 ctcctgggct caagcaatcc tcctgagtga tcccatttct taatcagtgt agccccaaga 
               
               
                   
               
               
                 1981 
                 aggctggggc tatttaccag ggtagaaaaa ggagcttacc tcccaccttt ggtcctaagt 
               
               
                   
               
               
                 2041 
                 ccctgccccc tccccttcac accataacta ggtaacagtt tgataactag ggaagaaagc 
               
               
                   
               
               
                 2101 
                 agaacagtta agcagccgcc acatccccgc tggctggggg cctcactcca ggaaggggct 
               
               
                   
               
               
                 2161 
                 ggactggctg tcctttccag tggcctggct ccgctgtgtg gatggggaga tcggggccag 
               
               
                   
               
               
                 2221 
                 aggcagaacc ctggtgagga agctccagtc ctgctctcta cccagcccat cttgcctcca 
               
               
                   
               
               
                 2281 
                 tggtgcctct ggaggcctct gggcctcctc taacaggggc tggtgggcac caagagccaa 
               
               
                   
               
               
                 2341 
                 tggagtagac ccctggctgg taagggccaa gtcccaccgg ttgcttctgg gaaggggttt 
               
               
                   
               
               
                 2401 
                 ctaacactag tctgtgtgct gtggttcctg gggtgccctc cactgccctc tgttcagtaa 
               
               
                   
               
               
                 2461 
                 cagggccttg ctaatcgggt tgtcactcaa caaaagtgct ttggatttaa gttactatcc 
               
               
                   
               
               
                 2521 
                 tggctttgcc caacctcagc aacctgtaag actgataatg aaataaatca tgttaatcct 
               
               
                   
               
               
                 2581 
                 agcaaaaaaa aaaaaaaa 
               
            
           
         
       
     
     By “MBP polypeptide” (or myelin basic protein) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. P02686. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 19) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 mgnhagkrel naekastnse tnrgesekkr nlgelsrtts ednevfgead anqnngtssq 
                   
               
               
                   
               
               
                 61 
                 dtavtdskrt adpknawqda hpadpgsrph lirlfsrdap gredntfkdr psesdelqti 
               
               
                   
               
               
                 121 
                 qedsaatses ldvmasqkrp sqrhgskyla tastmdharh gflprhrdtg ildsigrffg 
               
               
                   
               
               
                 181 
                 gdrgapkrgs gkdshhpart ahygslpqks hgrtqdenpv vhffknivtp rtpppsqgkg 
               
               
                   
               
               
                 241 
                 rglslsrfsw gaegqrpgfg yggrasdyks ahkgfkgvda qgtlskifkl ggrdsrsgsp 
               
               
                   
               
               
                 301 
                 marr 
               
            
           
         
       
     
     By “MBP nucleic acid molecule” (or myelin basic protein) is meant a polynucleotide (e.g., mRNA) encoding an MBP polypeptide. An exemplary MBP nucleic acid molecule is provided at NCBI Accession No. M13577. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 20) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 gaaaacagtg cagccacctc cgagagcctg gatgtgatgg cgtcacagaa gagaccctcc 
                   
               
               
                   
               
               
                 61 
                 cagaggcacg gatccaagta cctggccaca gcaagtacca tggaccatgc caggcatggc 
               
               
                   
               
               
                 121 
                 ttcctcccaa ggcacagaga cacgggcatc cttgactcca tcgggcgctt ctttggcggt 
               
               
                   
               
               
                 181 
                 gacaggggtg cgccaaagcg gggctctggc aaggactcac accacccggc aagaactgct 
               
               
                   
               
               
                 241 
                 cactatggct ccctgcccca gaagtcacac ggccggaccc aagatgaaaa ccccgtagtc 
               
               
                   
               
               
                 301 
                 cacttcttca agaacattgt gacgcctcgc acaccacccc cgtcgcaggg aaaggggaga 
               
               
                   
               
               
                 361 
                 ggactgtccc tgagcagatt tagctggggg gccgaaggcc agagaccagg atttggctac 
               
               
                   
               
               
                 421 
                 ggaggcagag cgtccgacta taaatcggct cacaagggat tcaagggagt cgatgcccag 
               
               
                   
               
               
                 481 
                 ggcacgcttt ccaaaatttt taagctggga ggaagagata gtcgctctgg atcacccatg 
               
               
                   
               
               
                 541 
                 gctagacgct gaaaacccac ctggttccgg aatcctgtcc tcagcttctt aatataactg 
               
               
                   
               
               
                 601 
                 ccttaaaact ttaatcccac ttgcccctgt tacctaatta gagcagatga cccctcccct 
               
               
                   
               
               
                 661 
                 aatgcctgcg gagttgtgca cgtagtaggg tcaggccacg gcagcctacc ggcaatttcc 
               
               
                   
               
               
                 721 
                 ggccaacagt taaatgagaa catgaaaaca gaaaacggtt aaaactgtcc ctttctgtgt 
               
               
                   
               
               
                 781 
                 gaagatcacg ttccttcccc cgcaatgtgc ccccagacgc acgtgggtct tcagggggcc 
               
               
                   
               
               
                 841 
                 aggtgcacag acgtccctcc acgttcaccc ctccaccctt ggactttctt ttcgccgtgg 
               
               
                   
               
               
                 901 
                 ctcggcaccc ttgcgctttt gctggtcact gccatggagg cacacagctg cagagacaga 
               
               
                   
               
               
                 961 
                 gaggacgtgg gcggcagaga ggactgttga catccaagct tcctttgttt ttttttcctg 
               
               
                   
               
               
                 1021 
                 tccttctctc acctcctaaa gtagacttca tttttcctaa caggattaga cagtcaagga 
               
               
                   
               
               
                 1081 
                 gtggcttact acatgtggga gctttttggt atgtgacatg cgggctgggc agctgttaga 
               
               
                   
               
               
                 1141 
                 gtccaacgtg gggcagcaca gagagggggc cacctcccca ggccgtggct gcccacacac 
               
               
                   
               
               
                 1201 
                 cccaattagc tgaattcgcg tgtggcagag ggaggaaaag gaggcaaacg tgggctgggc 
               
               
                   
               
               
                 1261 
                 aatggcctca cataggaaac agggtcttcc tggagatttg gtgatggaga tgtcaagcag 
               
               
                   
               
               
                 1321 
                 gtggcctctg gacgtcaccg ttgccctgca tggtggcccc agagcagcct ctatgaacaa 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 1381 
                 cctcgtttcc aaaccacagc ccacagccgg agagtccagg aagacttgcg cactcagagc 
                   
                   
               
               
                   
               
               
                 1441 
                 agaagggtag gagtcctcta gacagcctcg cagccgcgcc agtcgcccat agacactggc 
                   
               
               
                   
               
               
                 1501 
                 tgtgaccggg cgtgctggca gcggcagtgc acagtggcca gcactaaccc tccctgagaa 
                   
               
               
                   
               
               
                 1561 
                 gataaccggc tcattcactt cctcccagaa gacgcgtggt agcgagtagg cacaggcgtg 
                   
               
               
                   
               
               
                 1621 
                 cacctgctcc cgaattactc accgagacac acgggctgag cagacggccc ctgtgatgga 
                   
               
               
                   
               
               
                 1681 
                 gacaaagagc tcttctgacc atatccttct taacacccgc tggcatctcc tttcgcgcct 
                   
               
               
                   
               
               
                 1741 
                 ccctccctaa cctactgacc caccttttga ttttagcgca cctgtgattg ataggccttc 
                   
               
               
                   
               
               
                 1801 
                 caaagagtcc cacgctggca tcaccctccc cgaggacgga gatgaggagt agtcagcgtg 
                   
               
               
                   
               
               
                 1861 
                 atgccaaaac gcgtcttctt aatccaattc taattctgaa tgtttcgtgt gggcttaata 
                   
               
               
                   
               
               
                 1921 
                 ccatgtctat taatatatag cctcgatgat gagagagtta caaagaacaa aactccagac 
                   
               
               
                   
               
               
                 1981 
                 acaaacctcc aaatttttca gcagaagcac tctgcgtcgc tgagctgagg tcggctctgc 
                   
               
               
                   
               
               
                 2041 
                 gatccatacg tggccgcacc cacacagcac gtgctgtgac gatggctgaa cggaaagtgt 
                   
               
               
                   
               
               
                 2101 
                 acactgttcc tgaatattga aataaaacaa taaactttt 
                   
               
            
           
         
       
     
     By “TUBIII polypeptide” (or TUBB3, tubulin beta chain 3) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. NP_001184110. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 21) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 mdsvrsgafg hlfrpdnfif gqsgagnnwa kghytegael vdsvldvvrk ecencdclqg 
                   
               
               
                   
               
               
                 61 
                 fqlthslggg tgsgmgtlli skvreeypdr imntfsvvps pkvsdtvvep ynatlsihql 
               
               
                   
               
               
                 121 
                 ventdetyci dnealydicf rtlklatpty gdlnhlvsat msgvttslrf pgqlnadlrk 
               
               
                   
               
               
                 181 
                 lavnmvpfpr lhffmpgfap ltargsqqyr altvpeltqq mfdaknmmaa cdprhgrylt 
               
               
                   
               
               
                 241 
                 vatvfrgrms mkevdeqmla iqsknssyfv ewipnnvkva vcdipprglk msstfignst 
               
               
                   
               
               
                 301 
                 aiqelfkris eqftamfrrk aflhwytgeg mdemefteae snmndlvsey qqyqdataee 
               
               
                   
               
               
                 361 
                 egemyeddee eseaqgpk 
               
            
           
         
       
     
     By “TUBIII nucleic acid molecule” (or TUBB3, tubulin beta chain 3) is meant a polynucleotide (e.g., mRNA) encoding an TUBIII polypeptide. An exemplary TUBIII nucleic acid molecule is provided at NCBI Accession No. BC000748. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 22) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 gcccggcccg cccgcgcccg tccgcagccg cccgccagac gcgcccagta tgagggagat 
                   
               
               
                   
               
               
                 61 
                 cgtgcacatc caggccggcc agtgcggcaa ccagatcggg gccaagttct gggaagtcat 
               
               
                   
               
               
                 121 
                 cagtgatgag catggcatcg accccagcgg caactacgtg ggcgactcgg acttgcagct 
               
               
                   
               
               
                 181 
                 ggagcggatc agcgtctact acaacgaggc ctcttctcac aagtacgtgc ctcgagccat 
               
               
                   
               
               
                 241 
                 tctggtggac ctggaacccg gaaccatgga cagtgtccgc tcaggggcct ttggacatct 
               
               
                   
               
               
                 301 
                 cttcaggcct gacaatttca tctttggtca gagtggggcc ggcaacaact gggccaaggg 
               
               
                   
               
               
                 361 
                 tcactacacg gagggggcgg agctggtgga ttcggtcctg gatgtggtgc ggaaggagtg 
               
               
                   
               
               
                 421 
                 tgaaaactgc gactgcctgc agggcttcca gctgacccac tcgctggggg gcggcacggg 
               
               
                   
               
               
                 481 
                 ctccggcatg ggcacgttgc tcatcagcaa ggtgcgtgag gagtatcccg accgcatcat 
               
               
                   
               
               
                 541 
                 gaacaccttc agcgtcgtgc cctcacccaa ggtgtcagac acggtggtgg agccctacaa 
               
               
                   
               
               
                 601 
                 cgccacgctg tccatccacc agctggtgga gaacacggat gagacctact gcatcgacaa 
               
               
                   
               
               
                 661 
                 cgaggcgctc tacgacatct gcttccgcac cctcaagctg gccacgccca cctacgggga 
               
               
                   
               
               
                 721 
                 cctcaaccac ctggtatcgg ccaccatgag cggagtcacc acctccttgc gcttcccggg 
               
               
                   
               
               
                 781 
                 ccagctcaac gctgacctgc gcaagctggc cgtcaacatg gtgcccttcc cgcgcctgca 
               
               
                   
               
               
                 841 
                 cttcttcatg cccggcttcg cccccctcac agcccggggc agccagcagt accgggccct 
               
               
                   
               
               
                 901 
                 gaccgtgccc gagctcaccc agcagatgtt cgatgccaag aacatgatgg ccgcctgcga 
               
               
                   
               
               
                 961 
                 cccgcgccac ggccgctacc tgacggtggc caccgtgttc cggggccgca tgtccatgaa 
               
               
                   
               
               
                 1021 
                 ggaggtggac gagcagatgc tggccatcca gagcaagaac agcagctact tcgtggagtg 
               
               
                   
               
               
                 1081 
                 gatccccaac aacgtgaagg tggccgtgtg tgacatcccg ccccgcggcc tcaagatgtc 
               
               
                   
               
               
                 1141 
                 ctccaccttc atcgggaaca gcacggccat ccaggagctg ttcaagcgca tctccgagca 
               
               
                   
               
               
                 1201 
                 gttcacggcc atgttccggc gcaaggcctt cctgcactgg tacacgggcg agggcatgga 
               
               
                   
               
               
                 1261 
                 cgagatggag ttcaccgagg ccgagagcaa catgaacgac ctggtgtccg agtaccagca 
               
               
                   
               
               
                 1321 
                 gtaccaggac gccacggccg aggaagaggg cgagatgtac gaagacgacg aggaggagtc 
               
               
                   
               
               
                 1381 
                 ggaggcccag ggccccaagt gaagctgctc gcagctggag tgagaggcag gtggcggccg 
               
               
                   
               
               
                 1441 
                 gggccgaagc cagcagtgtc taaacccccg gagccatctt gctgccgaca ccctgctttc 
               
               
                   
               
               
                 1501 
                 ccctcgccct agggctccct tgccgccctc ctgcagtatt tatggcctcg tcctccccac 
               
               
                   
               
               
                 1561 
                 ctaggccacg tgtgagctgc tcctgtctct gtcttattgc agctccaggc ctgacgtttt 
               
               
                   
               
               
                 1621 
                 acggttttgt tttttactgg tttgtgttta tattttcggg gatacttaat aaatctattg 
               
               
                   
               
               
                 1681 
                 ctgtcagata cccttaaaaa aaaaaaaaaa aaaaaaaaaa 
               
            
           
         
       
     
     By “NEUN polypeptide” (or Feminizing Locus on X-3, Fox-3, RNA-binding protein fox-1 homolog 3, or Hexaribonucleotide Binding Protein-3) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. NP_001076044. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 23) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 maqpyppaqy ppppqngipa eyapppphpt qdysgqtpvp tehgmtlytp aqthpeqpgs 
                   
               
               
                   
               
               
                 61 
                 eastqpiagt qtvpqtdeaa qtdsqplhps dptekqqpkr lhvsnipfrf rdpdlrqmfg 
               
               
                   
               
               
                 121 
                 qfgkildvei ifnergskgf gfvtfetssd adrareklng tivegrkiev nnatarvmtn 
               
               
                   
               
               
                 181 
                 kktgnpytng wklnpvvgav ygpefyavtg fpypttgtav ayrgahlrgr gravyntfra 
               
               
                   
               
               
                 241 
                 apppppipty gavvyqdgfy gaeiyggyaa yryaqpaaaa aaysdsygrv yaaadpyhht 
               
               
                   
               
               
                 301 
                 igpaatysig tm 
               
            
           
         
       
     
     By “NEUN nucleic acid molecule” (or Feminizing Locus on X-3, Fox-3, RNA-binding protein fox-1 homolog 3, or Hexaribonucleotide Binding Protein-3) is meant a polynucleotide (e.g., mRNA) encoding an NEUN polypeptide. An exemplary NEUN nucleic acid molecule is provided at NCBI Accession No. NM_001082575. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 24) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 gatacagcag cagctggtgc tcctggccag gctgtgcgtg ctctctctgc ctctctctct 
                   
               
               
                   
               
               
                 61 
                 cggactctct gctctctctc tctgactctc tcctctctct ctgttggcct ggtgaaatgt 
               
               
                   
               
               
                 121 
                 tcttggctgt aggcacacag agccttggac tcaaggctgt tggagtcgag gacaccttga 
               
               
                   
               
               
                 181 
                 cttcggtcct ggaggttgaa attctgcctc tgagaagcta acagtcttcc tgtggtcgcc 
               
               
                   
               
               
                 241 
                 actcctcccc agcagccccc tccttgccaa ggacggtcca gaaggagccc cactggggcc 
               
               
                   
               
               
                 301 
                 tccccgctca gcaaagcaga cctcacctcc cactaccagc ttgaagtcac agcagccaga 
               
               
                   
               
               
                 361 
                 ggaaattctg ccaccatttt cccaggtctg cagcccctcc agctgggaac ctgctcctgg 
               
               
                   
               
               
                 421 
                 agccatccct ctgcaaacag agagcccaga gtgcctcggg gaaaattggc tgaataaaag 
               
               
                   
               
               
                 481 
                 agcgatcagg acgccacggc tccgcctgaa gcgatggccc agccctaccc ccccgcccag 
               
               
                   
               
               
                 541 
                 tacccccctc cgccacagaa cggcatccct gccgagtacg ccccgccccc accgcacccc 
               
               
                   
               
               
                 601 
                 acgcaggact actccggcca gaccccggtc cccacagagc atggcatgac cctgtacaca 
               
               
                   
               
               
                 661 
                 ccagcacaga cccaccccga gcagccaggc tccgaggcca gcacacagcc catcgccggg 
               
               
                   
               
               
                 721 
                 acccagacag tgccgcagac agacgaggcg gcacagacgg acagccagcc gctccacccc 
               
               
                   
               
               
                 781 
                 tccgacccta cagagaagca gcagcccaag cggctacacg tctccaacat ccccttccgg 
               
               
                   
               
               
                 841 
                 ttcagggacc ccgacttgcg gcaaatgttc gggcaattcg gaaaaatttt agacgtggag 
               
               
                   
               
               
                 901 
                 atcattttta acgagcgggg ctccaagggt tttgggtttg taacttttga aactagctca 
               
               
                   
               
               
                 961 
                 gatgctgacc gagcccggga gaagctgaat gggacgatcg tagagggacg gaaaattgag 
               
               
                   
               
               
                 1021 
                 gtcaataatg ccacggcccg agtgatgacc aacaagaaga cggggaaccc ctacaccaac 
               
               
                   
               
               
                 1081 
                 ggctggaagc taaatccagt ggtcggcgca gtctacgggc ctgaattcta tgcagtgacg 
               
               
                   
               
               
                 1141 
                 gggttcccct accccaccac cggcacagcc gttgcctacc ggggcgcaca tcttcggggc 
               
               
                   
               
               
                 1201 
                 cggggccggg ccgtgtataa tacatttcgg gctgcgccac ccccaccccc catcccgact 
               
               
                   
               
               
                 1261 
                 tacggagcgg tcgtgtatca ggatggattt tatggtgctg agatttatgg aggctacgca 
               
               
                   
               
               
                 1321 
                 gcctacagat acgctcagcc cgctgcagcg gcggcagcct acagcgacag ttacggcaga 
               
               
                   
               
               
                 1381 
                 gtctacgcag ctgccgaccc gtaccatcac accatcgggc ccgcggcgac ctacagcatt 
               
               
                   
               
               
                 1441 
                 ggaaccatgt gaaaccttcc accgtttcct tctcggacca tgaagggcaa aaacaaaaaa 
               
               
                   
               
               
                 1501 
                 acaaaaaaaa tcacaaaaca aaaaaaacaa aaaaagatgt taagatccaa gcaacaaaaa 
               
               
                   
               
               
                 1561 
                 aaaaaccaac caaaccaaga ggcatccaac caagtccaag tcccgcgtcc tggccacacg 
               
               
                   
               
               
                 1621 
                 cccgcaccga gggagcacgc cggcaggggc gccgaggagc ggccccagga caggacggcc 
               
               
                   
               
               
                 1681 
                 ccaccgcgtc ctggctggca gcacagtggg aacacgcccc tccgtctcag gcagtggggg 
               
               
                   
               
               
                 1741 
                 agttggaggg gaaggggcct cccttgtggg acccgtgggg ggctctgttt tccatccagt 
               
               
                   
               
               
                 1801 
                 cttcctttcc cagcccccaa ctcccaagac agacagtgtg gagcccagcg gcggcggagc 
               
               
                   
               
               
                 1861 
                 aggcccgggc ctgagcaggc aggcgctgct agcaagactt gatctttgtg gccagctgtg 
               
               
                   
               
               
                 1921 
                 ccagggggcc ggcggggctg aggggtgcgg gcagctttca tcccaggggc tccactgggc 
               
               
                   
               
               
                 1981 
                 cccgtcaccc tcctgtcgcg tcccctgcgt cccacctccc tcctgcccgg cagtcccgcc 
               
               
                   
               
               
                 2041 
                 cgtgccccca gcctggcgag gaagccgtcc aacagtagcc ccggggccag ctcccaacag 
               
               
                   
               
               
                 2101 
                 aaagggctga cgtggctcca ggactcaggg gcgctccatg ggaggacgaa ggaagcccag 
               
               
                   
               
               
                 2161 
                 ccagccagga gccactcctc acacctccaa gtgtggccaa gtgggccctg aggccaagga 
               
               
                   
               
               
                 2221 
                 cttacttgct cttcctggcc atctctccct ttctggagga ggcccggggc ctgtgtacac 
               
               
                   
               
               
                 2281 
                 caaggctgac ctcgtgctgc ctgctgggac ccagccctcc ctgccgctcc cctgtgagcc 
               
               
                   
               
               
                 2341 
                 cagtccaccg tgggcgccca gggccaggga cgggccagcg cccggctgca tcgcgaggtt 
               
               
                   
               
               
                 2401 
                 gggagtcaca gtggctgtgg gcctggacgg gcacagccag agcaggggcc catgggaagg 
               
               
                   
               
               
                 2461 
                 gcaagggatg gggaagcctg ggccggcccc ttccctgctc ccaaggcagg tgtccaggtg 
               
               
                   
               
               
                 2521 
                 gcgggagcag caccaaggac agccaggctt acccggtggg aggagcagga gcagagcagg 
               
               
                   
               
               
                 2581 
                 tggcagggag gaacccctgg cgaggcaggg agcactgaag tagggaagca gcaaaaaata 
               
               
                   
               
               
                 2641 
                 caggctccca acgtggctcc actgtctcat gaagtgtcaa aaatttaaaa atacacctca 
               
               
                   
               
               
                 2701 
                 ctttctattc agcatcagct attgaaatgg aattctcctt ttctattccc gttgtacata 
               
               
                   
               
               
                 2761 
                 gccccacgcc ctgcctccgg ctttgtcctc tgtacagagc cccctgtccc ctctgctgtt 
               
               
                   
               
               
                 2821 
                 ccggaccctt ttcttgcagc agctcaaccc cccgactcac tcagatcccc aggactgcag 
               
               
                   
               
               
                 2881 
                 ccgagccccg ggcttccttt cttaccattc tgtatgcttc caaggtgtga ccattcaaac 
               
               
                   
               
               
                 2941 
                 taacagtatt attaagatta ttaataaaga tttctttctt caaaccagga aaaaaaaaaa 
               
               
                   
               
               
                 3001 
                 aaaaaaa 
               
            
           
         
       
     
     By “SLC1A6 polypeptide” (or Excitatory amino acid transporter 4; Sodium-dependent glutamate/aspartate transporter; Solute carrier family 1 member 6) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. P48664. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 25) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 msshgnslfl resgqrlgry gwlqrlqesl qqralrtrlr lqtmtlehvl rflrrnafil 
                   
               
               
                   
               
               
                 61 
                 ltvsavvigv slafalrpyq ltyrqikyfs fpgellmrml qmlvlplivs slvtgmasld 
               
               
                   
               
               
                 121 
                 nkatgrmgmr aavyymvtti iavfigilmv tiihpgkgsk eglhregrie tiptadafmd 
               
               
                   
               
               
                 181 
                 lirnmfppnl veacfkqfkt qystrvvtrt mvrtengsep gasmpppfsv engtsflenv 
               
               
                   
               
               
                 241 
                 tralgtlqem lsfeetvpvp gsanginalg lvvfsvafgl viggmkhkgr vlrdffdsln 
               
               
                   
               
               
                 301 
                 eaimrlvgii iwyapvgilf liagkileme dmavlggqlg mytltvivgl flhagivlpl 
               
               
                   
               
               
                 361 
                 iyflvthrnp fpfiggmlqa litamgtsss satlpitfrc leeglgvdrr itrfvlpvga 
               
               
                   
               
               
                 421 
                 tvnmdgtaly ealaaifiaq vnnyelnlgq ittisitata asvgaagipq aglvtmvivl 
               
               
                   
               
               
                 481 
                 tsvglptedi tliiavdwfl drlrtmtnvl gdsigaavie hlsqrelelq eaeltlpslg 
               
               
                   
               
               
                 541 
                 kpykslmaqe kgasrgrggn esam 
               
            
           
         
       
     
     By “SLC1A6 nucleic acid molecule” (or Excitatory amino acid transporter 4; Sodium-dependent glutamate/aspartate transporter; Solute carrier family 1 member 6) is meant a polynucleotide (e.g., mRNA) encoding an SLC1A6 polypeptide. An exemplary SLC1A6 nucleic acid molecule is provided at NCBI Accession No. BC040604. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 26) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 ggcatagcgc gtcccggctc cgcgccggtg cctccacggt ccggtccccg cgccggtgct 
                   
               
               
                   
               
               
                 61 
                 gcacagtccc tggcgggtcc ccgcggcccc ggccgggcgc ttcgccgggc tccggctcct 
               
               
                   
               
               
                 121 
                 gcatccgggc gcagcgcgca ggccgaggcg cgggcaggcc gcccccgccg ctccggacgc 
               
               
                   
               
               
                 181 
                 cgggatgtaa gaggctccga aaagcagccc acgcatctca tcagatctaa gtgtctagag 
               
               
                   
               
               
                 241 
                 gtcgggagaa ccaagtggga aagacccacc ctcacccctc accttgtaga aactgggaac 
               
               
                   
               
               
                 301 
                 actagaaggg acattttctg agcaggaaac ccaagagaca gggttttacg ctgtcaccca 
               
               
                   
               
               
                 361 
                 agttggagtg cagtggtacg atcatagctc attgcagcct caaactcctg ggttcaagcg 
               
               
                   
               
               
                 421 
                 atcctcctgc tttagcctct tgagtagcta ggactacagg cacaggccac cgtgcctggc 
               
               
                   
               
               
                 481 
                 taatttttaa tttttaaaaa agagacaggg tctggctatg ttgcccaggc tggccatgaa 
               
               
                   
               
               
                 541 
                 ctcctgggct caagcggttc tccagccttc acctcccaaa gtgttgggat tgcaggcatg 
               
               
                   
               
               
                 601 
                 agccactgcg tctggcccac agatgctaag tgctgtctgc tcttctccag gggtcagcaa 
               
               
                   
               
               
                 661 
                 attttttcag caaatggccc aagagtaaat attttgagct ttgtggcccg tacaatctct 
               
               
                   
               
               
                 721 
                 gtcccaacaa ctcaactcag gcattgtagc ttgaaagcag ctgtagacaa taggtaatcc 
               
               
                   
               
               
                 781 
                 atgagtgtgg ctgtgtgcca ataaaacttt atttacaaaa acaagcagta ggctgaattt 
               
               
                   
               
               
                 841 
                 gactagcaga ccatagtttg tcaataccgt attatgtctt gtaaggaaga gaaaggaacc 
               
               
                   
               
               
                 901 
                 agacaaaact ctagcctcgg gagttttcct gactgttcag atcttagctg aatgatctcc 
               
               
                   
               
               
                 961 
                 cttggtatct acaggcaact tcctgctgtg gcttagggac tggaaacata atatcccaga 
               
               
                   
               
               
                 1021 
                 gggattccct gtgtagtctg tggttcactc tttgggattt tttttttttt tttcacagca 
               
               
                   
               
               
                 1081 
                 aggagaagca gcattgtggt ttcaggagat gggtccattt ggagcaggat cctaagtggg 
               
               
                   
               
               
                 1141 
                 gcttggcatt gggaatttgg attagctcta gaggacgcag gatctggaaa atcagggcag 
               
               
                   
               
               
                 1201 
                 atttcccatc ccttggatat ggtggggagt tgaggagggc aaggaagatc ccagaaaagc 
               
               
                   
               
               
                 1261 
                 cagtggcagc aaaacacaaa ggccagggac ctacgtactg gtaaaactga gacctccaag 
               
               
                   
               
               
                 1321 
                 aaacctgcag ctcgacctgg ttgaattcag atagaccatg agcagccatg gcaacagcct 
               
               
                   
               
               
                 1381 
                 gttccttcgg gagagcggcc agcggctggg ccgggtgggc tggctgcagc ggctgcagga 
               
               
                   
               
               
                 1441 
                 aagcctgcag cagagagcac tgcgcacgcg cctgcgcctg cagaccatga ccctcgagca 
               
               
                   
               
               
                 1501 
                 cgtgctgcgc ttcctgcgcc gaaacgcctt cattctgctg acggtcagcg ccgtggtcat 
               
               
                   
               
               
                 1561 
                 tggggtcagc ctggcctttg ccctgcgccc atatcagctc acctaccgcc agatcaagta 
               
               
                   
               
               
                 1621 
                 cttctctttt cctggagagc ttctgatgag gatgctgcag atgctggtgt tacctctcat 
               
               
                   
               
               
                 1681 
                 tgtctccagc ctggtcacag gtatggcatc cctggacaac aaggccacgg ggcggatggg 
               
               
                   
               
               
                 1741 
                 gatgcgggca gctgtgtact acatggtgac caccatcatc gcggtcttca tcggcatcct 
               
               
                   
               
               
                 1801 
                 catggtcacc atcatccatc ccgggaaggg ctccaaggag gggctgcacc gggagggccg 
               
               
                   
               
               
                 1861 
                 gatcgagacc atccccacag ctgatgcctt catggacctg atcagaaata tgtttccacc 
               
               
                   
               
               
                 1921 
                 aaaccttgtg gaggcctgct tcaaacagtt caagacgcag tacagcacga gggtggtaac 
               
               
                   
               
               
                 1981 
                 caggaccatg gtgaggacag agaacgggtc tgagccgggt gcctccatgc ctcctccatt 
               
               
                   
               
               
                 2041 
                 ctcagtggag aacggaacca gcttcctgga aaatgtcact cgggccttgg gtaccctgca 
               
               
                   
               
               
                 2101 
                 ggagatgctg agctttgagg agactgtacc cgtgcctggc tccgccaatg gcatcaacgc 
               
               
                   
               
               
                 2161 
                 cctgggcctc gtggtcttct ctgtggcctt tgggctggtc attggtggca tgaaacacaa 
               
               
                   
               
               
                 2221 
                 gggcagagtc ctcagggact tcttcgacag cctcaatgag gctattatga ggctggtggg 
               
               
                   
               
               
                 2281 
                 catcattatc tggtgagtcc tggtctgtgc ccacgggaag gtggagccag agctgggaag 
               
               
                   
               
               
                 2341 
                 tcaggctgtg gggaagctgc cgaagggctt gctggggacc tttggtcatt catttacgta 
               
               
                   
               
               
                 2401 
                 ttgggtgatt cacttaccca ctcaccaact cattcattca tgtctttctg ggatgatttc 
               
               
                   
               
               
                 2461 
                 atcactagtt cacttccttg ttcatctgtt cattcattca ttcttctatg cattggttag 
               
               
                   
               
               
                 2521 
                 ttcatggaat atctcactct ttcattcatt catgtccttc tgcaatgatt cattcactgc 
               
               
                   
               
               
                 2581 
                 tttgttcatc tgttcattca ctcattcttc tatgcattga tgaaatcact cattcagtga 
               
               
                   
               
               
                 2641 
                 tttattcatc tatactcatg cttcaatgca ttgatttact catttcctca tgcatttatt 
               
               
                   
               
               
                 2701 
                 cattcatcta tgcattggtt aaatcactgg ccaactcact aactcattca ttcattcaca 
               
               
                   
               
               
                 2761 
                 cttttctgca atgatttgtt cacttgttca ctcccttgct tatctgttca ttcactcatt 
               
               
                   
               
               
                 2821 
                 cttcaataca ttgaccaagc cattcactga catttattca gctacattta ttctttcatg 
               
               
                   
               
               
                 2881 
                 cattggtctg gatttatttg gtcattcatt tatttatttt gcaaaattaa tgtattttta 
               
               
                   
               
               
                 2941 
                 attgacaaat aaaaactgta tatattttca tgtgcaaaaa aaaaaaaaaa 
               
            
           
         
       
     
     By “NOGOA polypeptide” (or neurite outgrowth inhibitor A; neurite outgrowth inhibitor isoform A; human reticulon-4; human reticulon-4 isoform A) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. 
     NP_065393. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 27) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 medldqsplv sssdspprpq pafkyqfvre pedeeeeeee eeedededle elevlerkpa 
                   
               
               
                   
               
               
                 61 
                 aglsaapvpt apaagaplmd fgndfvppap rgplpaappv aperqpswdp spvsstvpap 
               
               
                   
               
               
                 121 
                 splsaaaysp sklpeddepp arppppppas vspqaepvwt ppapapaapp stpaapkrrg 
               
               
                   
               
               
                 181 
                 ssgsvdetlf alpaasepvi rssaenmdlk eqpgntisag qedfpsvlle taaslpslsp 
               
               
                   
               
               
                 241 
                 lsaasfkehe ylgnlstvlp tegtlqenvs easkevseka ktllidrdlt efseleysem 
               
               
                   
               
               
                 301 
                 gssfsyspka esavivanpr eeiivknkde eeklvsnnil hnqqelptal tklykedevv 
               
               
                   
               
               
                 361 
                 ssekakdsfn ekrvaveapm reeyadfkpf ervwevkdsk edsdmlaagg kiesnleskv 
               
               
                   
               
               
                 421 
                 dkkcfadsle qtnhekdses snddtsfpst pegikdrsga yitcapfnpa atesiatnif 
               
               
                   
               
               
                 481 
                 pllgdptsen ktdelddeek kaqivteknt stktsnpflv aaqdsetdyv ttdnitkvte 
               
               
                   
               
               
                 541 
                 evvanmpegl tpdlvqeace selnevtgtk iayetkmdlv qtsevmqesl ypaaqlcpsf 
               
               
                   
               
               
                 601 
                 eeseatpspv lpdivmeapl nsavpsagas viqpsssple assvnyesik hepenpppye 
               
               
                   
               
               
                 661 
                 eamsyslkkv sgikeeikep eninaalqet eapyisiacd liketklsae papdfsdyse 
               
               
                   
               
               
                 721 
                 makveqpvpd hselvedssp dsepvdlfsd dsipdvpqkq detvmlvkes ltetsfesmi 
               
               
                   
               
               
                 781 
                 eyenkeklsa lppeggkpyl esfklsldnt kdtllpdevs tlskkekipl qmeelstavy 
               
               
                   
               
               
                 841 
                 snddlfiske aqiretetfs dsspieiide fptlissktd sfsklareyt dlevshksei 
               
               
                   
               
               
                 901 
                 anapdgagsl pctelphdls lkniqpkvee kisfsddfsk ngsatskyll lppdvsalat 
               
               
                   
               
               
                 961 
                 qaeiesivkp kvlvkeaekk lpsdtekedr spsaifsael sktsvvdlly wrdikktgvv 
               
               
                   
               
               
                 1021 
                 fgaslfllls ltvfsivsvt ayialallsv tisfriykgv iqaiqksdeg hpfraylese 
               
               
                   
               
               
                 1081 
                 vaiseelvqk ysnsalghvn ctikelrrlf lvddlvdslk favlmwvfty vgalfngltl 
               
               
                   
               
               
                 1141 
                 lilalislfs vpviyerhqa qidhylglan knvkdamaki qakipglkrk ae 
               
            
           
         
       
     
     By “NOGOA nucleic acid molecule” (or neurite outgrowth inhibitor A; neurite outgrowth inhibitor isoform A; human reticulon-4; human reticulon-4 isoform A) is meant a polynucleotide encoding an NOGOA polypeptide. An exemplary NOGOA nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. NM_020532. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 28) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 agtccctgcc ctcccctggg gagggtgagt cacgccaaac tgggcggaga gtccgctggc 
                   
               
               
                   
               
               
                 61 
                 ctcactccta gctcatctgg gcggcggcgg caagtgggga cagggcgggt ggcgcatcac 
               
               
                   
               
               
                 121 
                 cggcgcggag gcaggaggag cagtctcatt gttccgggag ccgtcaccac agtaggtccc 
               
               
                   
               
               
                 181 
                 tcggctcagt cggcccagcc cctctcagtc ctccccaacc cccacaaccg cccgcggctc 
               
               
                   
               
               
                 241 
                 tgagacgcgg ccccggcggc ggcggcagca gctgcagcat catctccacc ctccagccat 
               
               
                   
               
               
                 301 
                 ggaagacctg gaccagtctc ctctggtctc gtcctcggac agcccacccc ggccgcagcc 
               
               
                   
               
               
                 361 
                 cgcgttcaag taccagttcg tgagggagcc cgaggacgag gaggaagaag aggaggagga 
               
               
                   
               
               
                 421 
                 agaggaggac gaggacgaag acctggagga gctggaggtg ctggagagga agcccgccgc 
               
               
                   
               
               
                 481 
                 cgggctgtcc gcggccccag tgcccaccgc ccctgccgcc ggcgcgcccc tgatggactt 
               
               
                   
               
               
                 541 
                 cggaaatgac ttcgtgccgc cggcgccccg gggacccctg ccggccgctc cccccgtcgc 
               
               
                   
               
               
                 601 
                 cccggagcgg cagccgtctt gggacccgag cccggtgtcg tcgaccgtgc ccgcgccatc 
               
               
                   
               
               
                 661 
                 cccgctgtct gctgccgcag tctcgccctc caagctccct gaggacgacg agcctccggc 
               
               
                   
               
               
                 721 
                 ccggcctccc cctcctcccc cggccagcgt gagcccccag gcagagcccg tgtggacccc 
               
               
                   
               
               
                 781 
                 gccagccccg gctcccgccg cgcccccctc caccccggcc gcgcccaagc gcaggggctc 
               
               
                   
               
               
                 841 
                 ctcgggctca gtggatgaga ccctttttgc tcttcctgct gcatctgagc ctgtgatacg 
               
               
                   
               
               
                 901 
                 ctcctctgca gaaaatatgg acttgaagga gcagccaggt aacactattt cggctggtca 
               
               
                   
               
               
                 961 
                 agaggatttc ccatctgtcc tgcttgaaac tgctgcttct cttccttctc tgtctcctct 
               
               
                   
               
               
                 1021 
                 ctcagccgct tctttcaaag aacatgaata ccttggtaat ttgtcaacag tattacccac 
               
               
                   
               
               
                 1081 
                 tgaaggaaca cttcaagaaa atgtcagtga agcttctaaa gaggtctcag agaaggcaaa 
               
               
                   
               
               
                 1141 
                 aactctactc atagatagag atttaacaga gttttcagaa ttagaatact cagaaatggg 
               
               
                   
               
               
                 1201 
                 atcatcgttc agtgtctctc caaaagcaga atctgccgta atagtagcaa atcctaggga 
               
               
                   
               
               
                 1261 
                 agaaataatc gtgaaaaata aagatgaaga agagaagtta gttagtaata acatccttca 
               
               
                   
               
               
                 1321 
                 taatcaacaa gagttaccta cagctcttac taaattggtt aaagaggatg aagttgtgtc 
               
               
                   
               
               
                 1381 
                 ttcagaaaaa gcaaaagaca gttttaatga aaagagagtt gcagtggaag ctcctatgag 
               
               
                   
               
               
                 1441 
                 ggaggaatat gcagacttca aaccatttga gcgagtatgg gaagtgaaag atagtaagga 
               
               
                   
               
               
                 1501 
                 agatagtgat atgttggctg ctggaggtaa aatcgagagc aacttggaaa gtaaagtgga 
               
               
                   
               
               
                 1561 
                 taaaaaatgt tttgcagata gccttgagca aactaatcac gaaaaagata gtgagagtag 
               
               
                   
               
               
                 1621 
                 taatgatgat acttctttcc ccagtacgcc agaaggtata aaggatcgtt caggagcata 
               
               
                   
               
               
                 1681 
                 tatcacatgt gctcccttta acccagcagc aactgagagc attgcaacaa acatttttcc 
               
               
                   
               
               
                 1741 
                 tttgttagga gatcctactt cagaaaataa gaccgatgaa aaaaaaatag aagaaaagaa 
               
               
                   
               
               
                 1801 
                 ggcccaaata gtaacagaga agaatactag caccaaaaca tcaaaccctt ttcttgtagc 
               
               
                   
               
               
                 1861 
                 agcacaggat tctgagacag attatgtcac aacagataat ttaacaaagg tgactgagga 
               
               
                   
               
               
                 1921 
                 agtcgtggca aacatgcctg aaggcctgac tccagattta gtacaggaag catgtgaaag 
               
               
                   
               
               
                 1981 
                 tgaattgaat gaagttactg gtacaaagat tgcttatgaa acaaaaatgg acttggttca 
               
               
                   
               
               
                 2041 
                 aacatcagaa gttatgcaag agtcactcta tcctgcagca cagctttgcc catcatttga 
               
               
                   
               
               
                 2101 
                 agagtcagaa gctactcctt caccagtttt gcctgacatt gttatggaag caccattgaa 
               
               
                   
               
               
                 2161 
                 ttctgcagtt cctagtgctg gtgcttccgt gatacagccc agctcatcac cattagaagc 
               
               
                   
               
               
                 2221 
                 ttcttcagtt aattatgaaa gcataaaaca tgagcctgaa aaccccccac catatgaaga 
               
               
                   
               
               
                 2281 
                 ggccatgagt gtatcactaa aaaaagtatc aggaataaag gaagaaatta aagagcctga 
               
               
                   
               
               
                 2341 
                 aaatattaat gcagctcttc aagaaacaga agctccttat atatctattg catgtgattt 
               
               
                   
               
               
                 2401 
                 aattaaagaa acaaagcttt ctgctgaacc agctccggat ttctctgatt attcagaaat 
               
               
                   
               
               
                 2461 
                 ggcaaaagtt gaacagccag tgcctgatca ttctgagcta gttgaagatt cctcacctga 
               
               
                   
               
               
                 2521 
                 ttctgaacca gttgacttat ttagtgatga ttcaatacct gacgttccac aaaaacaaga 
               
               
                   
               
               
                 2581 
                 tgaaactgtg atgcttgtga aagaaagtct cactgagact tcatttgagt caatgataga 
               
               
                   
               
               
                 2641 
                 atatgaaaat aaggaaaaac tcagtgcttt gccacctgag ggaggaaagc catatttgga 
               
               
                   
               
               
                 2701 
                 atcttttaag ctcagtttag ataacacaaa agataccctg ttacctgatg aagtttcaac 
               
               
                   
               
               
                 2761 
                 attgagcaaa aaggagaaaa ttcctttgca gatggaggag ctcagtactg cagtttattc 
               
               
                   
               
               
                 2821 
                 aaatgatgac ttatttattt ctaaggaagc acagataaga gaaactgaaa cgttttcaga 
               
               
                   
               
               
                 2881 
                 ttcatctcca attgaaatta tagatgagtt ccctacattg atcagttcta aaactgattc 
               
               
                   
               
               
                 2941 
                 attttctaaa ttagccaggg aatatactga cctagaagta tcccacaaaa gtgaaattgc 
               
               
                   
               
               
                 3001 
                 taatgccccg gatggagctg ggtcattgcc ttgcacagaa ttgccccatg acctttcttt 
               
               
                   
               
               
                 3061 
                 gaagaacata caacccaaag ttgaagagaa aatcagtttc tcagatgact tttctaaaaa 
               
               
                   
               
               
                 3121 
                 tgggtctgct acatcaaagg tgctcttatt gcctccagat gtttctgctt tggccactca 
               
               
                   
               
               
                 3181 
                 agcagagata gagagcatag ttaaacccaa agttcttgtg aaagaagctg agaaaaaact 
               
               
                   
               
               
                 3241 
                 tccttccgat acagaaaaag aggacagatc accatctgct atattttcag cagagctgag 
               
               
                   
               
               
                 3301 
                 taaaacttca gttgttgacc tcctgtactg gagagacatt aagaagactg gagtggtgtt 
               
               
                   
               
               
                 3361 
                 tggtgccagc ctattcctgc tgctttcatt gacagtattc agcattgtga gcgtaacagc 
               
               
                   
               
               
                 3421 
                 ctacattgcc ttggccctgc tctctgtgac catcagcttt aggatataca agggtgtgat 
               
               
                   
               
               
                 3481 
                 ccaagctatc cagaaatcag atgaaggcca cccattcagg gcatatctgg aatctgaagt 
               
               
                   
               
               
                 3541 
                 tgctatatct gaggagttgg ttcagaagta cagtaattct gctcttggtc atgtgaactg 
               
               
                   
               
               
                 3601 
                 cacgataaag gaactcaggc gcctcttctt agttgatgat ttagttgatt ctctgaagtt 
               
               
                   
               
               
                 3661 
                 tgcagtgttg atgtgggtat ttacctatgt tggtgccttg tttaatggtc tgacactact 
               
               
                   
               
               
                 3721 
                 gattttggct ctcatttcac tcttcagtgt tcctgttatt tatgaacggc atcaggcaca 
               
               
                   
               
               
                 3781 
                 gatagatcat tatctaggac ttgcaaataa gaatgttaaa gatgctatgg ctaaaatcca 
               
               
                   
               
               
                 3841 
                 agcaaaaatc cctggattga agcgcaaagc tgaatgaaaa cgcccaaaat aattagtagg 
               
               
                   
               
               
                 3901 
                 agttcatctt taaaggggat attcatttga ttatacgggg gagggtcagg gaagaacgaa 
               
               
                   
               
               
                 3961 
                 ccttgacgtt gcagtgcagt ttcacagatc gttgttagat ctttattttt agccatgcac 
               
               
                   
               
               
                 4021 
                 tgttgtgagg aaaaattacc tgtcttgact gccatgtgtt catcatctta agtattgtaa 
               
               
                   
               
               
                 4081 
                 gctgctatgt atggatttaa accgtaatca tatctttttc ctatctatct gaggcactgg 
               
               
                   
               
               
                 4141 
                 tggaataaaa aacctgtata ttttactttg ttgcagatag tcttgccgca tcttggcaag 
               
               
                   
               
               
                 4201 
                 ttgcagagat ggtggagcta gaaaaaaaaa aaaaaaagcc cttttcagtt tgtgcactgt 
               
               
                   
               
               
                 4261 
                 gtatggtccg tgtagattga tgcagatttt ctgaaatgaa atgtttgttt agacgagatc 
               
               
                   
               
               
                 4321 
                 ataccggtaa agcaggaatg acaaagcttg cttttctggt atgttctagg tgtattgtga 
               
               
                   
               
               
                 4381 
                 cttttactgt tatattaatt gccaatataa gtaaatatag attatatatg tatagtgttt 
               
               
                   
               
               
                 4441 
                 cacaaagctt agacctttac cttccagcca ccccacagtg cttgatattt cagagtcagt 
               
               
                   
               
               
                 4501 
                 cattggttat acatgtgtag ttccaaagca cataagctag aagaagaaat atttctagga 
               
               
                   
               
               
                 4561 
                 gcactaccat ctgttttcaa catgaaatgc cacacacata gaactccaac atcaatttca 
               
               
                   
               
               
                 4621 
                 ttgcacagac tgactgtagt taattttgtc acagaatcta tggactgaat ctaatgcttc 
               
               
                   
               
               
                 4681 
                 caaaaatgtt gtttgtttgc aaatatcaaa cattgttatg caagaaatta ttaattacaa 
               
               
                   
               
               
                 4741 
                 aatgaagatt tataccattg tggtttaagc tgtactgaac taaatctgtg gaatgcattg 
               
               
                   
               
               
                 4801 
                 tgaactgtaa aagcaaagta tcaataaagc ttatagactt aaaaaaaaaa aaaaaaaaaa 
               
               
                   
               
               
                 4861 
                 aaaaaaaaaa a 
               
            
           
         
       
     
     By “oligodendrocyte 01 polypeptide” (or oligodendrocyte marker 01; oligodendrocyte transcription factor 1; olig1) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. Q8TAK6. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 29) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 myyavsqarv navpgtmlrp qrpgdlqlga slyelvgyrq ppssssssts stsstsssst 
                   
               
               
                   
               
               
                 61 
                 tapllpkaar ekpeapaepp gpgpgsgahp ggsarpdake eqqqqlrrki nsrerkrmqd 
               
               
                   
               
               
                 121 
                 lnlamdalre vilpysaahc qgapgrklsk iatlllarny illlgsslqe lrralgegag 
               
               
                   
               
               
                 181 
                 paaprlllag lpllaaapgs vllapgavgp pdalrpakyl slaldeppcg qfalpgggag 
               
               
                   
               
               
                 241 
                 gpglctcavc kfphlvpasl glaavqaqfs k 
               
            
           
         
       
     
     By “oligodendrocyte 01 nucleic acid molecule” (or oligodendrocyte marker 01; oligodendrocyte transcription factor 1; olig1) is meant a polynucleotide encoding an oligodendrocyte 01 polypeptide. An exemplary oligodendrocyte 01 nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. NM_138983. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 30) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 gttctagatc gtttccccgc gcgcaggtcc gcggggaggg gcggcctgcc gaccggccca 
                   
               
               
                   
               
               
                 61 
                 ccccagggcg ttcctgaagg gcgtcctcgg ccgcccccac cgcctcccag atgtactatg 
               
               
                   
               
               
                 121 
                 cggtttccca ggcgcgcgtg aacgcggtcc ccgggaccat gctgcggcca cagcggcccg 
               
               
                   
               
               
                 181 
                 gagacttgca gctcggggcc tccctctacg agctggtggg ctacaggcag ccgccctcct 
               
               
                   
               
               
                 241 
                 cctcctcctc ctccacctcc tccacctcct ccacttcctc ctcctccacg acggcccccc 
               
               
                   
               
               
                 301 
                 tcctccccaa ggctgcgcgc gagaagccgg aggcgccggc cgagcctcca ggccccgggc 
               
               
                   
               
               
                 361 
                 ccgggtcagg cgcgcacccg ggcggcagcg cccggccgga cgccaaggag gagcagcagc 
               
               
                   
               
               
                 421 
                 agcagctgcg gcgcaagatc aacagccgcg agcggaagcg catgcaggac ctgaacctgg 
               
               
                   
               
               
                 481 
                 ccatggacgc cctgcgcgag gtcatcctgc cctactcagc ggcgcactgc cagggcgcgc 
               
               
                   
               
               
                 541 
                 ccggccgcaa gctctccaag atagccacgc tgctgctcgc ccgcaactac atcctactgc 
               
               
                   
               
               
                 601 
                 tgggcagctc gctgcaggag ctgcgccgcg cgctgggcga gggcgccggg cccgccgcgc 
               
               
                   
               
               
                 661 
                 cgcgcctgct gctggccggg ctgcccctgc tcgccgccgc gcccggctcc gtgctgctgg 
               
               
                   
               
               
                 721 
                 cgcccggcgc cgtaggaccc cccgacgcgc tgcgccccgc caagtacctg tcgctggcgc 
               
               
                   
               
               
                 781 
                 tggacgagcc gccgtgcggc cagttcgctc tccccggcgg cggcgcaggc ggccccggcc 
               
               
                   
               
               
                 841 
                 tctgcacctg cgccgtgtgc aagttcccgc acctggtccc ggccagcctg ggcctggccg 
               
               
                   
               
               
                 901 
                 ccgtgcaggc gcaattctcc aagtgagggc gggtctgggc ctggggcgcg acctcggccc 
               
               
                   
               
               
                 961 
                 ggcctccctt cgctcagctt ctccgcgccc ctgctccctg cgtctgggag agcgaggccg 
               
               
                   
               
               
                 1021 
                 agcaaggaaa gcatttcgaa ccttccagtc cagaggaagg gactgtcggg cacccccttc 
               
               
                   
               
               
                 1081 
                 cccgccccca cccctgggac gttaaagtga ccagagcgga tgttcgatgg cgcctcgggg 
               
               
                   
               
               
                 1141 
                 cagtttgggg ttctgggtcg gttccagcgg ctttaggcag aaagtgctcg ctctcaccca 
               
               
                   
               
               
                 1201 
                 gcacatctct ctccttgtcc ctggagttgc gcgcttcgcg gggccgatgt agaacttagg 
               
               
                   
               
               
                 1261 
                 gcgccttgcc gtggttggcg cgccccgggt gcagcgagag gccatccccg agcgctacct 
               
               
                   
               
               
                 1321 
                 ccccggagcg gagcacgcgg gctcccagta ctaggggctg cgctcgagca gtggcggggg 
               
               
                   
               
               
                 1381 
                 cggaggggtg gttcttttcc ttctcctccg ccagaggcca cgggcgccct tgttcccgcc 
               
               
                   
               
               
                 1441 
                 ggccaggtcc tatcaaagga ggctgccgga actcaagagg cagaaaaaga ccagttaggc 
               
               
                   
               
               
                 1501 
                 ggtgcagacg gtctgggacg tggcagacgg acggaccctc ggcggacagg tggtcggcgt 
               
               
                   
               
               
                 1561 
                 cggggtgcgg tgggtagggg cgaggacaac gcagggtgcg ctgggttggg acgtgggtcc 
               
               
                   
               
               
                 1621 
                 acttttgtag accagctgtt tggagagctg tatttaagac tcgcgtatcc agtgttttgt 
               
               
                   
               
               
                 1681 
                 cgcagagagt tttcactctt aaatcctggg ggtttcttag aaagcaactt agaactcgag 
               
               
                   
               
               
                 1741 
                 attcaccttt cgtttccctt tccccaaaag tagcgtaacc aacatttaag cttgcttaaa 
               
               
                   
               
               
                 1801 
                 aacgaaaacc aaccgccttg catccagtgt tcccgattta ctaaaatagg taaccaggcg 
               
               
                   
               
               
                 1861 
                 tctcacagtc gccgtcctgt caagagcgct aatgaacgtt ctcattaaca cgcaggagta 
               
               
                   
               
               
                 1921 
                 ccgggagccc tgaaccgccc gctgctcggc ggatcccagc tgcggtggcg acggcgggaa 
               
               
                   
               
               
                 1981 
                 ggcgctttcc gctgttcctc agcgggccgg gcccttgacc agcgcggccc gcaggtcttc 
               
               
                   
               
               
                 2041 
                 cttctcgccg tcttgcagtt gaagagctac atacgtagtc agtttcgatt tgttacagac 
               
               
                   
               
               
                 2101 
                 gttaacaaat tcctttaccc aaggttatgc tatgaccttt ccgcagttta ctttgatttt 
               
               
                   
               
               
                 2161 
                 ctatgtttaa ggttttggtt gttggtagta gccgaattta actggcactt tattttactt 
               
               
                   
               
               
                 2221 
                 ctaaccttgt ttcctgacgg tgtacagaat caacaaaata aaacatttaa agtctgattt 
               
               
                   
               
               
                 2281 
                 tttaaaaaaa aaaaaaaa 
               
            
           
         
       
     
     By “oligodendrocyte 02 polypeptide” (or oligodendrocyte marker 02; oligodendrocyte transcription factor 2; olig2) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. Q13516. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 31) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 mdsdaslvss rpsspepddl flparskgss gsaftggtvs sstpsdcppe lsaelrgamg 
                   
               
               
                   
               
               
                 61 
                 sagahpgdkl ggsgfkssss stssstssaa asstkkdkkq mtepelqqlr lkinsrerkr 
               
               
                   
               
               
                 121 
                 mhdlniamdg lrevmpyahg psvrklskia tlllarnyil mltnsleemk rlvseiyggh 
               
               
                   
               
               
                 181 
                 hagfhpsacg glahsaplpa atahpaaaah aahhpavhhp ilppaaaaaa aaaaaaavss 
               
               
                   
               
               
                 241 
                 aslpgsglps vgsirpphgl lkspsaaaaa plggggggsg asggfqhwgg mpcpcsmcqv 
               
               
                   
               
               
                 301 
                 ppphhhvsam gagslprlts dak 
               
            
           
         
       
     
     By “oligodendrocyte 02 nucleic acid molecule” (or oligodendrocyte marker 02; oligodendrocyte transcription factor 2; olig2) is meant a polynucleotide encoding an oligodendrocyte 02 polypeptide. An exemplary oligodendrocyte 02 nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. NM_005806. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 32) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 gggtgcttat tatagatcga cgcgacacca gcgcccggtg ccaggttctc ccctgaggct 
                   
               
               
                   
               
               
                 61 
                 tttcggagcg agctcctcaa atcgcatcca gagtaagtgt ccccgcccca cagcagccgc 
               
               
                   
               
               
                 121 
                 agcctagatc ccagggacag actctcctca actcggctgt gacccagaat gctccgatac 
               
               
                   
               
               
                 181 
                 agggggtctg gatccctact ctgcgggcca tttctccaga gcgactttgc tcttctgtcc 
               
               
                   
               
               
                 241 
                 tccccacact caccgctgca tctccctcac caaaagcgag aagtcggagc gacaacagct 
               
               
                   
               
               
                 301 
                 ctttctgccc aagccccagt cagctggtga gctccccgtg gtctccagat gcagcacatg 
               
               
                   
               
               
                 361 
                 gactctgggc cccgcgccgg ctctgggtgc atgtgcgtgt gcgtgtgttt gctgcgtggt 
               
               
                   
               
               
                 421 
                 gtcgatggag ataaggtgga tccgtttgag gaaccaaatc attagttctc tatttagatc 
               
               
                   
               
               
                 481 
                 tccattctcc ccaaagaaag gccctcactt cccactcgtt tattccagcc cgggggctca 
               
               
                   
               
               
                 541 
                 gttttcccac acctaactga aagcccgaag cctctagaat gccacccgca ccccgagggt 
               
               
                   
               
               
                 601 
                 caccaacgct ccctgaaata acctgttgca tgagagcaga ggggagatag agagagctta 
               
               
                   
               
               
                 661 
                 attataggta cccgcgtgca gctaaaagga gggccagaga tagtagcgag ggggacgagg 
               
               
                   
               
               
                 721 
                 agccacgggc cacctgtgcc gggaccccgc gctgtggtac tgcggtgcag gcgggagcag 
               
               
                   
               
               
                 781 
                 cttttctgtc tctcactgac tcactctctc tctctctccc tctctctctc tctcattctc 
               
               
                   
               
               
                 841 
                 tctcttttct cctcctctcc tggaagtttt cgggtccgag ggaaggagga ccctgcgaaa 
               
               
                   
               
               
                 901 
                 gctgcgacga ctatcttccc ctggggccat ggactcggac gccagcctgg tgtccagccg 
               
               
                   
               
               
                 961 
                 cccgtcgtcg ccagagcccg atgacctttt tctgccggcc cggagtaagg gcagcagcgg 
               
               
                   
               
               
                 1021 
                 cagcgccttc actgggggca ccgtgtcctc gtccaccccg agtgactgcc cgccggagct 
               
               
                   
               
               
                 1081 
                 gagcgccgag ctgcgcggcg ctatgggctc tgcgggcgcg catcctgtgg acaagctagg 
               
               
                   
               
               
                 1141 
                 aggcagtggc ttcaagtcat cctcgtccag cacctcgtcg tctacgtcgt cggcggctgc 
               
               
                   
               
               
                 1201 
                 gtcgtccacc aagaaggaca agaagcaaat gacagagccg gagctgcagc agctgcgtct 
               
               
                   
               
               
                 1261 
                 caagatcaac agccgcgagc gcaagcgcat gcacgacctc aacatcgcca tggatggcct 
               
               
                   
               
               
                 1321 
                 ccgcgaggtc atgccgtacg cacacggccc ttcggtgcgc aagctttcca agatcgccac 
               
               
                   
               
               
                 1381 
                 gctgctgctg gcgcgcaact acatcctcat gctcaccaac tcgctggagg agatgaagcg 
               
               
                   
               
               
                 1441 
                 actggtgagc gagatctacg ggggccacca cgctggcttc cacccgtcgg cctgcggcgg 
               
               
                   
               
               
                 1501 
                 cctggcgcac tccgcgcccc tgcccgccgc caccgcgcac ccggcagcag cagcgcacgc 
               
               
                   
               
               
                 1561 
                 cgcacatcac cccgcggtgc accaccccat cctgccgccc gccgccgcag cggctgctgc 
               
               
                   
               
               
                 1621 
                 cgccgctgca gccgcggctg tgtccagcgc ctctctgccc ggatccgggc tgccgtcggt 
               
               
                   
               
               
                 1681 
                 cggctccatc cgtccaccgc acggcctact caagtctccg tctgctgccg cggccgcccc 
               
               
                   
               
               
                 1741 
                 gctggggggc gggggcggcg gcagtggggc gagcgggggc ttccagcact ggggcggcat 
               
               
                   
               
               
                 1801 
                 gccctgcccc tgcagcatgt gccaggtgcc gccgccgcac caccacgtgt cggctatggg 
               
               
                   
               
               
                 1861 
                 cgccggcagc ctgccgcgcc tcacctccga cgccaagtga gcctactggc gccggcgcgt 
               
               
                   
               
               
                 1921 
                 tctggcgaca ggggagccag gggccgcggg gaagcgagga ctggcctgcg ctgggctcgg 
               
               
                   
               
               
                 1981 
                 gagctctgtc gcgaggaggg gcgcaggacc atggactggg ggtggggcat ggtggggatt 
               
               
                   
               
               
                 2041 
                 tcagcatctg cgaacccaag caatgggggc gcccacagag cagtggggag tgaggggatg 
               
               
                   
               
               
                 2101 
                 ttctctccgg gacctgatcg agcgctgtct ggctttaacc tgagctggtc cagtagacat 
               
               
                   
               
               
                 2161 
                 cgttttatga aaaggtaccg ctgtgtgcat tcctcactag aactcatccg acccccgacc 
               
               
                   
               
               
                 2221 
                 cccacctccg ggaaaagatt ctaaaaactt ctttccctga gagcgtggcc tgacttgcag 
               
               
                   
               
               
                 2281 
                 actcggcttg ggcagcactt cgggggggga gggggtgtta tgggaggggg acacattggg 
               
               
                   
               
               
                 2341 
                 gccttgctcg tcttcctcct ttcttggcgg gtgggagact ccgggtagcc gcactgcaga 
               
               
                   
               
               
                 2401 
                 agcaacagcc cgaccgcgcc ctccagggtc gtccctggcc caaggccagg ggccacaagt 
               
               
                   
               
               
                 2461 
                 tagttggaag ccggcgttcg gtatcagaag cgctgatggt catatccaat ctcaatatct 
               
               
                   
               
               
                 2521 
                 gggtcaatcc acaccctctt agaactgtgg ccgttcctcc ctgtctctcg ttgatttggg 
               
               
                   
               
               
                 2581 
                 agaatatggt tttctaataa atctgtggat gttccttctt caacagtatg agcaagttta 
               
               
                   
               
               
                 2641 
                 tagacattca gagtagaacc acttgtggat tggaataacc caaaactgcc gatttcaggg 
               
               
                   
               
               
                 2701 
                 gcgggtgcat tgtagttatt attttaaaat agaaactacc ccaccgactc atctttcctt 
               
               
                   
               
               
                 2761 
                 ctctaagcac aaagtgattt ggttattttg gtacctgaga acgtaacaga attaaaaggc 
               
               
                   
               
               
                 2821 
                 agttgctgtg gaaacagttt gggttatttg ggggttctgt tggcttttta aaattttctt 
               
               
                   
               
               
                 2881 
                 ttttggatgt gtaaatttat caatgatgag gtaagtgcgc aatgctaagc tgtttgctca 
               
               
                   
               
               
                 2941 
                 cgtgactgcc agccccatcg gagtctaagc cggctttcct ctattttggt ttatttttgc 
               
               
                   
               
               
                 3001 
                 cacgtttaac acaaatggta aactcctcca cgtgcttcct gcgttccgtg caagccgcct 
               
               
                   
               
               
                 3061 
                 cggcgctgcc tgcgttgcaa actgggcttt gtagcgtctg ccgtgtaaca cccttcctct 
               
               
                   
               
               
                 3121 
                 gatcgcaccg cccctcgcag agagtgtatc atctgtttta tttttgtaaa aacaaagtgc 
               
               
                   
               
               
                 3181 
                 taaataatat ttattacttg tttggttgca aaaacggaat aaatgactga gtgttgagat 
               
               
                   
               
               
                 3241 
                 tttaaataaa atttaaagca aaaaaaaaaa aaaaa 
               
            
           
         
       
     
     By “oligodendrocyte 04 polypeptide” (or oligodendrocyte marker 04; oligodendrocyte transcription factor 4; olig4) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. Q05586. 
     By “oligodendrocyte 04 nucleic acid molecule” (or oligodendrocyte marker 04; oligodendrocyte transcription factor 4; olig4) is meant a polynucleotide encoding an oligodendrocyte 04 polypeptide. An exemplary oligodendrocyte 04 nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. NM_007327. 
     By “GFAP” (or Glial fibrillary acidic protein) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. P14136. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 33) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 merrritsaa rrsyvssgem mvgglapgrr lgpgtrlsla rmppplptry dfslagalna 
                   
               
               
                   
               
               
                 61 
                 gfketraser aemmelndrf asyiekvrfl eqqnkalaae lnqlrakept kladvyqael 
               
               
                   
               
               
                 121 
                 relrlrldql tansarleve rdnlaqdlat vrqklqdetn lrleaennla ayrqeadeat 
               
               
                   
               
               
                 181 
                 larldlerki esleeeirfl rkiheeevre lqeqlarqqv hveldvakpd ltaalkeirt 
               
               
                   
               
               
                 241 
                 qyeamassnm heaeewyrsk fadltdaaar naellrqakh eandyrrqlq sltcdleslr 
               
               
                   
               
               
                 301 
                 gtneslerqm reqeerhvre aasyqealar leeegqslkd emarhlqeyq dllnvklald 
               
               
                   
               
               
                 361 
                 ieiatyrkll egeenritip vqtfsnlqir etsldtksys eghlkrnivv ktvemrdgev 
               
               
                   
               
               
                 421 
                 ikeskqehkd vm 
               
            
           
         
       
     
     By “GFAP nucleic acid molecule” (or Glial fibrillary acidic protein) is meant a polynucleotide encoding an GFAP polypeptide. An exemplary GFAP nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. NM_002055. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 34) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 gcaggatgga gaggagacgc atcacctccg ctgctcgccg ctcctacgtc tcctcagggg 
                   
               
               
                   
               
               
                 61 
                 agatgatggt ggggggcctg gctcctggcc gccgtctggg tcctggcacc cgcctctccc 
               
               
                   
               
               
                 121 
                 tggctcgaat gccccctcca ctcccgaccc gagtggattt ctccctggct ggggcactca 
               
               
                   
               
               
                 181 
                 atgctggctt caaggagacc cgggccagtg agcgggcaga gatgatggag ctcaatgacc 
               
               
                   
               
               
                 241 
                 gctttgccag ctacatcgag aaggttcgct tcctggaaca gcaaaacaag gcgctggctg 
               
               
                   
               
               
                 301 
                 ctgagctgaa ccagctgcgg gccaaggagc ccaccaagct ggcagacgtc taccaggctg 
               
               
                   
               
               
                 361 
                 agctgcgaga gctgcggctg cggctcgatc aactcaccgc caacagcgcc cggctggagg 
               
               
                   
               
               
                 421 
                 ttgagaggga caatctggca caggacctgg ccactgtgag gcagaagctc caggatggaa 
               
               
                   
               
               
                 481 
                 ccaacctgag gctggaagcc gagaacaacc tggctgccta tagacaggaa gcagatgaag 
               
               
                   
               
               
                 541 
                 ccaccctggc ccgtctggat ctggagagga agattgagtc gctggaggag gagatccggt 
               
               
                   
               
               
                 601 
                 tcttgaggaa gatccacgag gaggaggttc gggaactcca ggagcagctg gcccgacagc 
               
               
                   
               
               
                 661 
                 aggtccatgt ggagcttgac gtggccaagc cagacctcac cgcagccctg aaagagatcc 
               
               
                   
               
               
                 721 
                 gcacgcagta tgaggcaatg gcgtccagca acatgcatga agccgaagag tggtaccgct 
               
               
                   
               
               
                 781 
                 ccaagtttgc agacctgaca gacgctgctg cccgcaacgc ggagctgctc cgccaggcca 
               
               
                   
               
               
                 841 
                 agcacgaagc caacgactac cggcgccagt tgcagtcctt gacctgcgac ctggagtctc 
               
               
                   
               
               
                 901 
                 tgcgcggcac gaacgagtcc ctggagaggc agatgcgcga gcaggaggag cggcacgtgc 
               
               
                   
               
               
                 961 
                 gggaggcggc cagttatcag gaggcgctgg cgcggctgga ggaagagggg cagagcctca 
               
               
                   
               
               
                 1021 
                 aggacgagat ggcccgccac ttgcaggagt accaggacct gctcaatgtc aagctggccc 
               
               
                   
               
               
                 1081 
                 tggacatcga gatcgccacc tacaggaagc tgctagaggg cgaggagaac cggatcacca 
               
               
                   
               
               
                 1141 
                 ttcccgtgca gaccttctcc aacctgcaga ttcgagaaac cagcctggac accaagtctg 
               
               
                   
               
               
                 1201 
                 tgtcagaagg ccacctcaag aggaacatcg tggtgaagac cgtggagatg cgggatggag 
               
               
                   
               
               
                 1261 
                 aggtcattaa ggagtccaag caggagcaca aggatgtgat gtgaggcagg acccacctgg 
               
               
                   
               
               
                 1321 
                 tggcctctgc cccgtctcat gaggggcccg agcagaagca ggatagttgc tccgcctctg 
               
               
                   
               
               
                 1381 
                 ctggcacatt tccccagacc tgagctcccc accaccccag ctgctcccct ccctcctctg 
               
               
                   
               
               
                 1441 
                 tccctaggtc agcttgctgc cctaggctcc gtcagtatca ggcctgcc 
               
            
           
         
       
     
     By “s110b” (or S-100 protein beta chain; S-100 protein subunit beta; S100 calcium-binding protein B) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. P04271. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 35) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 mselekamva lidvfhqysg regdkhklkk selkelinne lshfleeike qevvdkvmet 
                   
               
               
                   
               
               
                 61 
                 ldndgdgecd fqefmafvam vttacheffe he 
               
            
           
         
       
     
     By “s100b nucleic acid molecule” (or S-100 protein beta chain; S-100 protein subunit beta; S100 calcium-binding protein B) is meant a polynucleotide encoding an s100b polypeptide. An exemplary s100b nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. NM_006272. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 36) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 gggcagaggg aataagaggc tgcctctgcc caccagtcct gccgcccagg acccgcagca 
                   
               
               
                   
               
               
                 61 
                 gagacgacgc ctgcagcaag gagaccagga aggggtgaga caaggaagag gatgtctgag 
               
               
                   
               
               
                 121 
                 ctggagaagg ccatggtggc cctcatcgac gttttccacc aatattctgg aagggaggga 
               
               
                   
               
               
                 181 
                 gacaagcaca agctgaagaa atccgaactg aaggagctca tcaacaatga gctttcccat 
               
               
                   
               
               
                 241 
                 ttcttagagg aaatcaaaga gcaggaggtt gtggacaaag tcatggaaac actggacaat 
               
               
                   
               
               
                 301 
                 gatggagacg gcgaatgtga cttccaggaa ttcatggcct ttgttgccat ggttactact 
               
               
                   
               
               
                 361 
                 gcctgccacg agttctttga acatgagtga gattagaaag cagccaaacc tttcctgtaa 
               
               
                   
               
               
                 421 
                 cagagacggt catgcaagaa agcagacagc aagggcttgc agcctagtag gagctgagct 
               
               
                   
               
               
                 481 
                 ttccagccgt gttgtagcta attaggaagc ttgatttgct ttgtgattga aaaattgaaa 
               
               
                   
               
               
                 541 
                 acctctttcc aaaggctgtt ttaacggcct gcatcattct ttctgctata ttaggcctgt 
               
               
                   
               
               
                 601 
                 gtgtaagctg actggcccca gggactcttg ttaacagtaa cttaggagtc aggtctcagt 
               
               
                   
               
               
                 661 
                 gataaagcgt gcaccgtgca gcccgccatg gccgtgtaga ccctaacccg gagggaaccc 
               
               
                   
               
               
                 721 
                 tgactacaga aattaccccg gggcaccctt aaaacttcca ctacctttaa aaaacaaagc 
               
               
                   
               
               
                 781 
                 cttatccagc attatttgaa aacactgctg ttctttaaat gcgttcctca tccatgcaga 
               
               
                   
               
               
                 841 
                 taacagctgg ttggccggtg tggccctgca agggcgtggt ggcttcggcc tgcttcccgg 
               
               
                   
               
               
                 901 
                 gatgcgcctg atcaccaggt gaacgctcag cgctggcagc gctcctggaa aaagcaactc 
               
               
                   
               
               
                 961 
                 catcagaact cgcaatccga gccagctctg ggggctccag cgtggcctcc gtgacccatg 
               
               
                   
               
               
                 1021 
                 cgattcaagt cgcggctgca ggatccttgc ctccaacgtg cctccagcac atgcggcttc 
               
               
                   
               
               
                 1081 
                 cgagggcact accgggggct ctgagccacc gcgagggcct gcgttcaata aaaag 
               
            
           
         
       
     
     By “SOX10 polypeptide” (or SRY-related HMG-box transcription factor) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. NP_008872.1. 
     
       
         
           
               
            
               
                 (SEQ ID NO: 37) 
               
               
                 MAEEQDLSEVELSPVGSEEPRCLSPGSAPSLGPDGGGGGSGLRASPGPGE 
               
               
                   
               
               
                 LGKVKKEQQDGEADDDKFPVCIREAVSQVLSGYDWTLVPMPVRVNGASKS 
               
               
                   
               
               
                 KPHVKRPMNAFMVWAQAARRKLADQYPHLHNAELSKTLGKLWRLLNESDK 
               
               
                   
               
               
                 RPFIEEAERLRMQHKKDHPDYKYQPRRRKNGKAAQGEAECPGGEAEQGGT 
               
               
                   
               
               
                 AAIQAHYKSAHLDHRHPGEGSPMSDGNPEHPSGQSHGPPTPPTTPKTELQ 
               
               
                   
               
               
                 SGKADPKRDGRSMGEGGKPHIDFGNVDIGEISHEVMSNMETFDVAELDQY 
               
               
                   
               
               
                 LPPNGHPGHVSSYSAAGYGLGSALAVASGHSAWISKPPGVALPTVSPPGV 
               
               
                   
               
               
                 DAKAQVKTETAGPQGPPHYTDQPSTSQIAYTSLSLPHYGSAFPSISRPQF 
               
               
                   
               
               
                 DYSDHQPSGPYYGHSGQASGLYSAFSYMGPSQRPLYTAISDPSPSGPQSH 
               
               
                   
               
               
                 SPTHWEQPVYTTLSRP 
               
            
           
         
       
     
     By “SOX10 nucleic acid molecule” (or SRY-related HMG-box transcription factor) is meant a polynucleotide encoding an SOX10 polypeptide. An exemplary SOX10 nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. NM_006941.3. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 38) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 gtccggccag ggtggttggt ggtaaggatt caggctccgt cctaacgagg ccgtggcctg 
                   
               
               
                   
               
               
                 61 
                 aggctcaggg ccccccgccc ctccctccca gcccaccagc gtcacctccc agccccgagc 
               
               
                   
               
               
                 121 
                 tggaccgcac accttgggac acggttttcc acttcctaag gacgagcccc agactggagg 
               
               
                   
               
               
                 181 
                 agaggtccga ggaggtgggc gttggactct ttgcgaggac cccggcggct ggcccggggg 
               
               
                   
               
               
                 241 
                 aggcggccga ggcggcggcg gcggcggccg ggggcgacat ggcggaggag caggacctat 
               
               
                   
               
               
                 301 
                 cggaggtgga gctgagcccc gtgggctcgg aggagccccg ctgcctgtcc ccggggagcg 
               
               
                   
               
               
                 361 
                 cgccctcgct agggcccgac ggcggcggcg gcggatcggg cctgcgagcc agcccggggc 
               
               
                   
               
               
                 421 
                 caggcgagct gggcaaggtc aagaaggagc agcaggacgg cgaggcggac gatgacaagt 
               
               
                   
               
               
                 481 
                 tccccgtgtg catccgcgag gccgtcagcc aggtgctcag cggctacgac tggacgctgg 
               
               
                   
               
               
                 541 
                 tgcccatgcc cgtgcgcgtc aacggcgcca gcaaaagcaa gccgcacgtc aagcggccca 
               
               
                   
               
               
                 601 
                 tgaacgcctt catggtgtgg gctcaggcag cgcgcaggaa gctcgcggac cagtacccgc 
               
               
                   
               
               
                 661 
                 acctgcacaa cgctgagctc agcaagacgc tgggcaagct ctggaggctg ctgaacgaaa 
               
               
                   
               
               
                 721 
                 gtgacaagcg ccccttcatc gaggaggctg agcggctccg tatgcagcac aagaaagacc 
               
               
                   
               
               
                 781 
                 acccggacta caagtaccag cccaggcggc ggaagaacgg gaaggccgcc cagggcgagg 
               
               
                   
               
               
                 841 
                 cggagtgccc cggtggggag gccgagcaag gtgggaccgc cgccatccag gcccactaca 
               
               
                   
               
               
                 901 
                 agagcgccca cttggaccac cggcacccag gagagggctc ccccatgtca gatgggaacc 
               
               
                   
               
               
                 961 
                 ccgagcaccc ctcaggccag agccatggcc cacccacccc tccaaccacc ccgaagacag 
               
               
                   
               
               
                 1021 
                 agctgcagtc gggcaaggca gacccgaagc gggacgggcg ctccatgggg gagggcggga 
               
               
                   
               
               
                 1081 
                 agcctcacat cgacttcggc aacgtggaca ttggtgagat cagccacgag gtaatgtcca 
               
               
                   
               
               
                 1141 
                 acatggagac ctttgatgtg gctgagttgg accagtacct gccgcccaat gggcacccag 
               
               
                   
               
               
                 1201 
                 gccatgtgag cagctactca gcagccggct atgggctggg cagtgccctg gccgtggcca 
               
               
                   
               
               
                 1261 
                 gtggacactc cgcctggatc tccaagccac caggcgtggc tctgcccacg gtctcaccac 
               
               
                   
               
               
                 1321 
                 ctggtgtgga tgccaaagcc caggtgaaga cagagaccgc ggggccccag gggcccccac 
               
               
                   
               
               
                 1381 
                 actacaccga ccagccatcc acctcacaga tcgcctacac ctccctcagc ctgccccact 
               
               
                   
               
               
                 1441 
                 atggctcagc cttcccctcc atctcccgcc cccagtttga ctactctgac catcagccct 
               
               
                   
               
               
                 1501 
                 caggacccta ttatggccac tcgggccagg cctctggcct ctactcggcc ttctcctata 
               
               
                   
               
               
                 1561 
                 tggggccctc gcagcggccc ctctacacgg ccatctctga ccccagcccc tcagggcccc 
               
               
                   
               
               
                 1621 
                 agtcccacag ccccacacac tgggagcagc cagtatatac gacactgtcc cggccctaaa 
               
               
                   
               
               
                 1681 
                 gggggccctg tcgccaccac cccccgccca gcccctgccc ccagcctgtg tgccctgttc 
               
               
                   
               
               
                 1741 
                 cttgcccacc tcaggcctgg tggtggcagt ggaggaggct gaggaggctg aagaggctga 
               
               
                   
               
               
                 1801 
                 caggtcgggg ggctttctgt ctggctcact gccctgatga cccacccgcc ccatccaggc 
               
               
                   
               
               
                 1861 
                 tccagcagca aagccccagg agaacaggct ggacagagga gaaggaggtt gactgttgca 
               
               
                   
               
               
                 1921 
                 cccacactga aagatgaggg gctgcacctt cccccaggaa tgaccctcta tcccaggacc 
               
               
                   
               
               
                 1981 
                 tgagaagggc ctgctcaccc tcctcgggga ggggaagcac cagggttggt ggcatcggag 
               
               
                   
               
               
                 2041 
                 gccttaccac tcctatgact cctgttttct ctctcacaga tagtgagggt ctgacatgcc 
               
               
                   
               
               
                 2101 
                 catgccacct atgccacagt gcctaagggc taggccaccc agagactgtg cccggagctg 
               
               
                   
               
               
                 2161 
                 gccgtgtctc ccactcaggg gctgagagta gctttgagga gcctcattgg ggagtggggg 
               
               
                   
               
               
                 2221 
                 gttcgaggga cttagtggag ttctcatccc ttcaatgccc cctccctttc tgaaggcagg 
               
               
                   
               
               
                 2281 
                 aaggagttgg cacagaggcc ccctgatcca attctgtgcc aataacctca ttctttgtct 
               
               
                   
               
               
                 2341 
                 gagaaacagc ccccagtcct cctccactac aacctccatg accttgagac gcatcccagg 
               
               
                   
               
               
                 2401 
                 aggtgacgag gcaggggctc caggaaagga atcagagaca attcacagag cctccctccc 
               
               
                   
               
               
                 2461 
                 tgggctcctt gccagctccc tcttccctta ctaggctcta tggcccctgc tcagtcagcc 
               
               
                   
               
               
                 2521 
                 ccactccctg ggcttcccag agagtgacag ctgctcaggc cctaaccctt ggctccagga 
               
               
                   
               
               
                 2581 
                 gacacagggc ccagcaccca ggttgctgtc ggcaggctga agacactaga atcctgacct 
               
               
                   
               
               
                 2641 
                 gtacattctg cccttgcctc ttaccccttg cctcccagtg gtatttgaat aaagtatgta 
               
               
                   
               
               
                 2701 
                 gctatatctg cccctatttt cctgttctgc agccccccaa atccacatgt aactcattac 
               
               
                   
               
               
                 2761 
                 tgtctcctgt tatttatctc agtagtcccc tctcctagcc actctagccc ctattaactc 
               
               
                   
               
               
                 2821 
                 tgcattaagc attccacata ataaaattaa aggttccggt taaaaaaaaa aaaaaaaaaa 
               
               
                   
               
               
                 2881 
                 aa 
               
            
           
         
       
     
     By “SYN1 protein” (or Synaptin I protein) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to GenBank: AH006533.2. 
     
       
         
           
               
            
               
                 (SEQ ID NO: 39) 
               
               
                 MNYLRRRLSDSNFMANLPNGYMTDLQRPQPPPPPPGAHSPGATPGPGTAT 
               
               
                   
               
               
                 AERSSGVAPAASPAAPSPGSSGGGGFFSSLSNAVKQTTAAAAATFSEQVG 
               
               
                   
               
               
                 GGSGGAGRGGAASRVLLVIDEPHTDWAKYFKGKKIHGGIDIKVEQAEFSD 
               
               
                   
               
               
                 LNLVAHANGGFSVDMEVLRNGVKVVRSLKPDFVLIRQHAFSMARNGDYRS 
               
               
                   
               
               
                 LVIGLQYAGIPSVNSLHSVYNFCDKPWVFAQMVRLHKKLGTEEFPLIDQT 
               
               
                   
               
               
                 FYPNHKEMLSSTTYPVVVKMGHAHSGMGKVKVDNQHDFQDIASVVALTKT 
               
               
                   
               
               
                 YATAEPFIDAKYDVRVQKIGQNYKAYMRTSVSGNWKTNTGSAMLEQIAMS 
               
               
                   
               
               
                 DRYKLWVDTCSEIFGGLDICAVEALHGKDGRDHIIEVVGSSMPLIGDHQD 
               
               
                   
               
               
                 EDKQLIVELVVNKMAQALPRQRQRDASPGRGSHGQTPSPGALPLGRQTSQ 
               
               
                   
               
               
                 QPAGPPAQQRPPPQGGPPQPGPGPQRQGPPLQQRPPPQGQQHLSGLGPPA 
               
               
                   
               
               
                 GSPLPQRLPSPTSAPQQPASQAAPPTQGQGRQSRPVAGGPGAPPAARPPA 
               
               
                   
               
               
                 SPSPQRQAGPPQATRQTSVSGPAPPKASGAPPGGQQRQGPPQKPPGPAGP 
               
               
                   
               
               
                 TRQASQAGPVPRTGPPTTQQPRPSGPGPAGAPKPQLAQKPSQDVPPPATA 
               
               
                   
               
               
                 AAGGPPHPQLNKSQSLTNAFNLPEPAPPRPSLSQDEVKAETIRSLRKSFA 
               
               
                   
               
               
                 SLFSD 
               
            
           
         
       
     
     By “SYN1 nucleic acid molecule” (or synapsin I gene) is meant a polynucleotide encoding an SYN1 polypeptide. An exemplary SYN1 nucleic acid molecule (e.g., mRNA) is provided at GenBank: AH006533.2. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 40) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 ctcgagagag aaggagagga cattcctggc agaagttaca acacatgcaa aggtacagag 
                   
               
               
                   
               
               
                 61 
                 gttgccccct tcctacccct ctccttagag gtgggttaga gatgtatcct ttttacagat 
               
               
                   
               
               
                 121 
                 gaggaaacca aatctcagaa agattaagtc actttcccaa gtgtatggtg gaggccccac 
               
               
                   
               
               
                 181 
                 ttgaacccag gcactgtgtc tccagacccc acactattac tgccttgttt aaaccagcca 
               
               
                   
               
               
                 241 
                 actgatttaa tgaataaagg atgaacaaat gaataagtgg atgagtcacc tgaaaattct 
               
               
                   
               
               
                 301 
                 gcaggcaaag agactccata tctacttact tcttgcctat cttctgccac ctctcctagt 
               
               
                   
               
               
                 361 
                 ccaccatcac tgctcactat ggtcaaggtc ctacccaatc tggcccctgc taccacaacc 
               
               
                   
               
               
                 421 
                 cccttcagct tgttccagcc acattggcac tggatgtttc ctcttcctgg cacattctta 
               
               
                   
               
               
                 481 
                 aaaaaatgtg ttgatcataa agtgaacatg accctttggg aattaactgg agttcttgta 
               
               
                   
               
               
                 541 
                 ttccctcatc tgtaaaatag acattatatt atccacccca ctggattgtt gtgagggtgg 
               
               
                   
               
               
                 601 
                 gatgaaatga tgcatgtaaa cacgcttagc ttaagagttg ggtacaatca gtgaacaaat 
               
               
                   
               
               
                 661 
                 gattatgaat tagtgctttt attgtagtca gaatcataaa gatttgacag gttcccatat 
               
               
                   
               
               
                 721 
                 cccacctctg cttggactac ctcatttgct catatgcaaa gattatttgg tacctactgt 
               
               
                   
               
               
                 781 
                 gtgtgcacca tgggatgggc ctgcctctgt ggaaagttct tgggtgcagg gggagacagc 
               
               
                   
               
               
                 841 
                 catgggcact gatgacatca ggtagttatc gtgagttttg gcggtgtcca gagcaaaggg 
               
               
                   
               
               
                 901 
                 atggtggcgt atataccaag tgtgttctgg tgtgggggtg gacacgcacc agggctaggg 
               
               
                   
               
               
                 961 
                 ctgcagagaa tgtctgtgtt gcagatctag gtttctccat gatcatcggt gggaatgtgt 
               
               
                   
               
               
                 1021 
                 tttgtctgca agtgtatgct catatgagtt tccctgggtc tctgtgtgtc agtgtgttac 
               
               
                   
               
               
                 1081 
                 ctgtgtgtgt gggggtatgg gtgtatgcat gcatgtatgt aacatgccca tgtgtgttac 
               
               
                   
               
               
                 1141 
                 tctggacttg tatgtctgta tgtataccta gattggcgtg tgttctgtct gtacatgccc 
               
               
                   
               
               
                 1201 
                 tcgtatgttt cctcactttt gtgtgtgttt atatgtgtgt catttcttgt gtgccctcca 
               
               
                   
               
               
                 1261 
                 ggcccccctt gccaccttgg gcaagggtgt gtacaccacc caagtgtcca cctccgcttg 
               
               
                   
               
               
                 1321 
                 tctgatgctg tctgtgacgc ccccgctctc tgcctagctg agcctgtgtg gatgtgggag 
               
               
                   
               
               
                 1381 
                 actaatctcc ccgcgggcac tgcgtgtgac ctcacccccc tctgtgaggg ggttatttct 
               
               
                   
               
               
                 1441 
                 ctactttcgt gtctctgagt gtgcttccag tgcccccctc cccccaaaaa atgccttctg 
               
               
                   
               
               
                 1501 
                 agttgaatat caacactaca aaccgagtat ctgcagactg cagagggccc tgcgtatgag 
               
               
                   
               
               
                 1561 
                 tgcaagtggg ttttaggacc aggatgaggc ggggtggggg tgcctacctg acgaccgacc 
               
               
                   
               
               
                 1621 
                 ccgacccact ggacaagcac ccaaccccca ttccccaaat tgcgcatccc ctatcagaga 
               
               
                   
               
               
                 1681 
                 gggggagggg aaacaggatg cggcgaggcg cgtcgcgact gccagcttca gcaccgcgga 
               
               
                   
               
               
                 1741 
                 cagtgccttc gcccccgcct ggcggcgcgc gccaccgccg cctcagcact gaaggcgcgc 
               
               
                   
               
               
                 1801 
                 tgacgtcact cgccggtccc ccgcaaactc cccttcccgg ccaccttggt cgcgtccgcg 
               
               
                   
               
               
                 1861 
                 ccgccgccgg cccagccgga ccgcaccacg cgaggcgcga gatagggggg cacgggcgcg 
               
               
                   
               
               
                 1921 
                 accatctgcg ctgcggcgcc ggcgactcag cgctgcctca gtctgcggtg ggcagcggag 
               
               
                   
               
               
                 1981 
                 gagtcgtgtc gtgcctgaga gcgcagctgt gctcctgggc accgcgcagt ccgcccccgc 
               
               
                   
               
               
                 2041 
                 ggctcctggc cagaccaccc ctaggacccc ctgccccaag tcgcagccat gaactacctg 
               
               
                   
               
               
                 2101 
                 cggcgccgcc tgtcggacag caactttatg gccaatctgc caaatgggta catgacagac 
               
               
                   
               
               
                 2161 
                 ctgcagcgtc cgcagccgcc cccaccgccg cccggtgccc acagccccgg agccacgccc 
               
               
                   
               
               
                 2221 
                 ggtcccggga ccgccactgc cgagaggtcc tccggggtcg ccccagcggc ctctccggcc 
               
               
                   
               
               
                 2281 
                 gcccctagcc ccgggtcctc ggggggcggt ggcttcttct cgtcgctgtc caacgcggtc 
               
               
                   
               
               
                 2341 
                 aagcagacca cggcggcggc agctgccacc ttcagcgagc aggtgggcgg cggctctggg 
               
               
                   
               
               
                 2401 
                 ggcgcaggcc gcgggggagc cgcctccagg gtgctgctgg tcatcgacga gccgcacacc 
               
               
                   
               
               
                 2461 
                 gactggtaag 
               
            
           
         
       
     
     By “SYP protein” (or synaptophysin protein) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Reference Sequence: NM_003179.2. 
     
       
         
           
               
            
               
                 (SEQ ID NO: 41) 
               
               
                 MLLLADMDVVNQLVAGGQFRVVKEPLGFVKVLQWVFAIFAFATCGSYSGE 
               
               
                   
               
               
                 LQLSVDCANKTESDLSIEVEFEYPFRLHQVYFDAPTCRGGTTKVFLVGDY 
               
               
                   
               
               
                 SSSAEFFVTVAVFAFLYSMGALATYIFLQNKYRENNKGPMLDFLATAVFA 
               
               
                   
               
               
                 FMWLVSSSAWAKGLSDVKMATDPENIIKEMPVCRQTGNTCKELRDPVTSG 
               
               
                   
               
               
                 LNTSVVFGFLNLVLWVGNLWFVFKETGWAAPFLRAPPGAPEKQPAPGDAY 
               
               
                   
               
               
                 GDAGYGQGPGGYGPQDSYGPQGGYQPDYGQPAGSGGSGYGPQGDYGQQGY 
               
               
                   
               
               
                 GPQGAPTSFSNQM 
               
            
           
         
       
     
     By “SYP nucleic acid molecule” (or synaptophysin gene) is meant a polynucleotide encoding an SYN1 polypeptide. An exemplary SYP nucleic acid molecule (e.g., mRNA) is provided at NCBI Reference Sequence: NM_003179.2. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 42) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 gccccctgca ttgctgatgc tgctgctggc ggacatggac gtggtgaatc agctggtggc 
                   
               
               
                   
               
               
                 61 
                 tgggggtcag ttccgggtgg tcaaggagcc cctcggcttt gtgaaggtgc tgcaatgggt 
               
               
                   
               
               
                 121 
                 cttcgccatc ttcgcctttg ccacatgcgg cagctacagt ggggagctcc agctgagcgt 
               
               
                   
               
               
                 181 
                 ggattgtgcc aacaagaccg agagtgacct cagcatcgag gtcgagttcg agtacccctt 
               
               
                   
               
               
                 241 
                 caggctgcac caagtgtact ttgatgcacc cacctgccga gggggcacca ccaaggtctt 
               
               
                   
               
               
                 301 
                 cttagttggg gactactcct cgtcagccga attctttgtc accgtggccg tgtttgcctt 
               
               
                   
               
               
                 361 
                 cctctactcc atgggggctc tggccaccta catcttcctg cagaacaagt accgagagaa 
               
               
                   
               
               
                 421 
                 taacaaaggg cccatgctgg actttctggc cacggctgtg ttcgccttca tgtggctagt 
               
               
                   
               
               
                 481 
                 tagctcatcg gcatgggcca aggggctgtc agatgtgaag atggccacag acccagagaa 
               
               
                   
               
               
                 541 
                 cattatcaag gagatgcctg tctgccgcca gacagggaac acatgcaagg agctgagaga 
               
               
                   
               
               
                 601 
                 ccctgtgacc tcgggactca acacctcggt ggtgttcggc ttcctgaacc tggtgctctg 
               
               
                   
               
               
                 661 
                 ggtcggcaac ctgtggttcg tgtttaagga gacaggctgg gccgccccgt tcctgcgcgc 
               
               
                   
               
               
                 721 
                 gcctcccggc gcccccgaga aacaaccggc acccggggac gcctacggcg atgcaggcta 
               
               
                   
               
               
                 781 
                 cgggcagggc cccggcgggt acgggcccca ggattcctac gggcctcagg gcggctacca 
               
               
                   
               
               
                 841 
                 gcctgactat ggtcaaccag ccggcagcgg tggcagtggc tacgggcctc agggcgacta 
               
               
                   
               
               
                 901 
                 tgggcagcaa ggctacggcc cgcagggtgc acccacctcc ttctccaatc agatgtagtc 
               
               
                   
               
               
                 961 
                 tggtcagtga agcccaggag gacctggggg gggcaagagc tcaggagaag gcctgccccc 
               
               
                   
               
               
                 1021 
                 cttcccaccc ctatacccta ggtctccacc cctcaagcca ggagaccctg tctttgctgt 
               
               
                   
               
               
                 1081 
                 ttatatatat atatattata tataaatatc tatttatctg tctgagccct gccctcactc 
               
               
                   
               
               
                 1141 
                 cactcccctc atccactagg tgcccagtct tgagtgggcc ccctctctta ccccgtccct 
               
               
                   
               
               
                 1201 
                 ttccctgcat cccttggccc ctctctgttt accctccctg tcccctgagg ttaaggggat 
               
               
                   
               
               
                 1261 
                 ctaaaaggag gacagggagg gaacagacct cggctgtgtg gggagggtgg gcgtgacttc 
               
               
                   
               
               
                 1321 
                 agactctctc ctctctctcc ctccactcct cccaactctg gccttggttc ctccagcaat 
               
               
                   
               
               
                 1381 
                 gcctgcctga acaaaggccg ttagggaaat ccaactccag ggttaaagaa aggcagagat 
               
               
                   
               
               
                 1441 
                 tgggggggct tggggtagag aggacagttt aggacccaag gtggtcttgg agaggaggtg 
               
               
                   
               
               
                 1501 
                 tggagtggag gggtcagcag gggggttggg ttccagacag agtggatctg gagtctgaag 
               
               
                   
               
               
                 1561 
                 gagaggagtg cgctagagca ttctggggtg gggcttggaa gggcgctgag ggcagggttc 
               
               
                   
               
               
                 1621 
                 tagaaggggc gaggctttaa gcgaggcaga atggtgggct ccagagtagg tgggtcttgg 
               
               
                   
               
               
                 1681 
                 attggtacca gagcctatgg aaagggtgtg gcttggaaca tttgggagac tgagcttgat 
               
               
                   
               
               
                 1741 
                 tctaaagggg acagatcttg agcaaggcaa gaagtgggat tcaggaatgg gccaagccag 
               
               
                   
               
               
                 1801 
                 ggttccagac agggtggggc ttagaatggg gcttccatgg tggtttcaga aagggcagcc 
               
               
                   
               
               
                 1861 
                 cctccccatg gtgcagtgaa gaaaatgttt tacaatggct gggtttgggc agtggagagg 
               
               
                   
               
               
                 1921 
                 ggacttggat aggagcttcc agatgggttt tgttaggggt gggggagaat ggctctggct 
               
               
                   
               
               
                 1981 
                 acgacttggg acggaagtgg cctgagaaga gtcgagtgat atggcttgta gggtgaggcg 
               
               
                   
               
               
                 2041 
                 tgggatccag agagaagcac cccaccacac acacccttcc ccactcccgt gatgaaacag 
               
               
                   
               
               
                 2101 
                 ctaggttaat aggaggacag aaccaacggg tctgtgggac tggcccaccc ctcttccccc 
               
               
                   
               
               
                 2161 
                 ttcccctgcg ccctccctcc ctccacacct ccacccgtcc tggggtggtt ggaggcctgg 
               
               
                   
               
               
                 2221 
                 tctggagccc ctatcctgca ccctctgcta tgtctgtgat gtcagtagtg cctgtgatcg 
               
               
                   
               
               
                 2281 
                 tgtgttgcca ttttgtctgg ctgtggcccc tccttctccc ctccagaccc ctaccctttc 
               
               
                   
               
               
                 2341 
                 ccaaaccctt cggtattgtt caaagaaccc ccctccccaa ggaagaacaa atatgattct 
               
               
                   
               
               
                 2401 
                 cctctcccaa ataaactcct taaccaccta gtcaaaaaaa aaaaaaaaa 
               
            
           
         
       
     
     By “NOGOA polypeptide” (or neurite outgrowth inhibitor A; neurite outgrowth inhibitor isoform A; human reticulon-4; human reticulon-4 isoform A) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. NP_065393. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 43) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 medldqsplv sssdspprpq pafkyqfvre pedeeeeeee eeedededle elevlerkpa 
                   
               
               
                   
               
               
                 61 
                 aglsaapvpt apaagaplmd fgndfvppap rgplpaappv aperqpswdp spvsstvpap 
               
               
                   
               
               
                 121 
                 splsaaavsp sklpeddepp arppppppas vspqaepvwt ppapapaapp stpaapkrrg 
               
               
                   
               
               
                 181 
                 ssgsvdetlf alpaasepvi rssaenmdlk eqpgntisag qedfpsvlle taaslpslsp 
               
               
                   
               
               
                 241 
                 lsaasfkehe ylgnlstvlp tegtlqenvs easkevseka ktllidrdlt efseleysem 
               
               
                   
               
               
                 301 
                 gssfsvspka esavivanpr eeiivknkde eeklvsnnil hnqqelptal tklvkedevv 
               
               
                   
               
               
                 361 
                 ssekakdsfn ekrvaveapm reeyadfkpf ervwevkdsk edsdmlaagg kiesnleskv 
               
               
                   
               
               
                 421 
                 dkkcfadsle qtnhekdses snddtsfpst pegikdrsga yitcapfnpa atesiatnif 
               
               
                   
               
               
                 481 
                 pllgdptsen ktdekkieek kaqivteknt stktsnpflv aaqdsetdyv ttdnltkvte 
               
               
                   
               
               
                 541 
                 evvanmpegl tpdlvqeace selnevtgtk iayetkmdlv qtsevmqesl ypaaqlcpsf 
               
               
                   
               
               
                 601 
                 eeseatpspv lpdivmeapl nsavpsagas viqpsssple assvnyesik hepenpppye 
               
               
                   
               
               
                 661 
                 eamsvslkkv sgikeeikep eninaalqet eapyisiacd liketklsae papdfsdyse 
               
               
                   
               
               
                 721 
                 makveqpvpd hselvedssp dsepvdlfsd dsipdvpqkq detvmlvkes ltetsfesmi 
               
               
                   
               
               
                 781 
                 eyenkeklsa lppeggkpyl esfklsldnt kdtllpdevs tlskkekipl qmeelstavy 
               
               
                   
               
               
                 841 
                 snddlfiske aqiretetfs dsspieiide fptlissktd sfsklareyt dlevshksei 
               
               
                   
               
               
                 901 
                 anapdgagsl pctelphdls lkniqpkvee kisfsddfsk ngsatskvll lppdvsalat 
               
               
                   
               
               
                 961 
                 qaeiesivkp kvlvkeaekk lpsdtekedr spsaifsael sktsvvdlly wrdikktgvv 
               
               
                   
               
               
                 1021 
                 fgaslfllls ltvfsivsvt ayialallsv tisfriykgv iqaiqksdeg hpfraylese 
               
               
                   
               
               
                 1081 
                 vaiseelvqk ysnsalghvn ctikelrrlf lvddlvdslk favlmwvfty vgalfngltl 
               
               
                   
               
               
                 1141 
                 lilalislfs vpviyerhqa qidhylglan knvkdamaki qakipglkrk ae 
               
            
           
         
       
     
     By “NOGOA nucleic acid molecule” (or neurite outgrowth inhibitor A; neurite outgrowth inhibitor isoform A; human reticulon-4; human reticulon-4 isoform A) is meant a polynucleotide encoding an NOGOA polypeptide. An exemplary NOGOA nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. NM_020532. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 44) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 agtccctgcc ctcccctggg gagggtgagt cacgccaaac tgggcggaga gtccgctggc 
                   
               
               
                   
               
               
                 61 
                 ctcactccta gctcatctgg gcggcggcgg caagtgggga cagggcgggt ggcgcatcac 
               
               
                   
               
               
                 121 
                 cggcgcggag gcaggaggag cagtctcatt gttccgggag ccgtcaccac agtaggtccc 
               
               
                   
               
               
                 181 
                 tcggctcagt cggcccagcc cctctcagtc ctccccaacc cccacaaccg cccgcggctc 
               
               
                   
               
               
                 241 
                 tgagacgcgg ccccggcggc ggcggcagca gctgcagcat catctccacc ctccagccat 
               
               
                   
               
               
                 301 
                 ggaagacctg gaccagtctc ctctggtctc gtcctcggac agcccacccc ggccgcagcc 
               
               
                   
               
               
                 361 
                 cgcgttcaag taccagttcg tgagggagcc cgaggacgag gaggaagaag aggaggagga 
               
               
                   
               
               
                 421 
                 agaggaggac gaggacgaag acctggagga gctggaggtg ctggagagga agcccgccgc 
               
               
                   
               
               
                 481 
                 cgggctgtcc gcggccccag tgcccaccgc ccctgccgcc ggcgcgcccc tgatggactt 
               
               
                   
               
               
                 541 
                 cggaaatgac ttcgtgccgc cggcgccccg gggacccctg ccggccgctc cccccgtcgc 
               
               
                   
               
               
                 601 
                 cccggagcgg cagccgtctt gggacccgag cccggtgtcg tcgaccgtgc ccgcgccatc 
               
               
                   
               
               
                 661 
                 cccgctgtct gctgccgcag tctcgccctc caagctccct gaggacgacg agcctccggc 
               
               
                   
               
               
                 721 
                 ccggcctccc cctcctcccc cggccagcgt gagcccccag gcagagcccg tgtggacccc 
               
               
                   
               
               
                 781 
                 gccagccccg gctcccgccg cgcccccctc caccccggcc gcgcccaagc gcaggggctc 
               
               
                   
               
               
                 841 
                 ctcgggctca gtggatgaga ccctttttgc tcttcctgct gcatctgagc ctgtgatacg 
               
               
                   
               
               
                 901 
                 ctcctctgca gaaaatatgg acttgaagga gcagccaggt aacactattt cggctggtca 
               
               
                   
               
               
                 961 
                 agaggatttc ccatctgtcc tgcttgaaac tgctgcttct cttccttctc tgtctcctct 
               
               
                   
               
               
                 1021 
                 ctcagccgct tctttcaaag aacatgaata ccttggtaat ttgtcaacag tattacccac 
               
               
                   
               
               
                 1081 
                 tgaaggaaca cttcaagaaa atgtcagtga agcttctaaa gaggtctcag agaaggcaaa 
               
               
                   
               
               
                 1141 
                 aactctactc atagatagag atttaacaga gttttcagaa ttagaatact cagaaatggg 
               
               
                   
               
               
                 1201 
                 atcatcgttc agtgtctctc caaaagcaga atctgccgta atagtagcaa atcctaggga 
               
               
                   
               
               
                 1261 
                 agaaataatc gtgaaaaata aagatgaaga agagaagtta gttagtaata acatccttca 
               
               
                   
               
               
                 1321 
                 taatcaacaa gagttaccta cagctcttac taaattggtt aaagaggatg aagttgtgtc 
               
               
                   
               
               
                 1381 
                 ttcagaaaaa gcaaaagaca gttttaatga aaagagagtt gcagtggaag ctcctatgag 
               
               
                   
               
               
                 1441 
                 ggaggaatat gcagacttca aaccatttga gcgagtatgg gaagtgaaag atagtaagga 
               
               
                   
               
               
                 1501 
                 agatagtgat atgttggctg ctggaggtaa aatcgagagc aacttggaaa gtaaagtgga 
               
               
                   
               
               
                 1561 
                 taaaaaatgt tttgcagata gccttgagca aactaatcac gaaaaagata gtgagagtag 
               
               
                   
               
               
                 1621 
                 taatgatgat acttctttcc ccagtacgcc agaaggtata aaggatcgtt caggagcata 
               
               
                   
               
               
                 1681 
                 tatcacatgt gctcccttta acccagcagc aactgagagc attgcaacaa acatttttcc 
               
               
                   
               
               
                 1741 
                 tttgttagga gatcctactt cagaaaataa gaccgatgaa aaaaaaatag aagaaaagaa 
               
               
                   
               
               
                 1801 
                 ggcccaaata gtaacagaga agaatactag caccaaaaca tcaaaccctt ttcttgtagc 
               
               
                   
               
               
                 1861 
                 agcacaggat tctgagacag attatgtcac aacagataat ttaacaaagg tgactgagga 
               
               
                   
               
               
                 1921 
                 agtcgtggca aacatgcctg aaggcctgac tccagattta gtacaggaag catgtgaaag 
               
               
                   
               
               
                 1981 
                 tgaattgaat gaagttactg gtacaaagat tgcttatgaa acaaaaatgg acttggttca 
               
               
                   
               
               
                 2041 
                 aacatcagaa gttatgcaag agtcactcta tcctgcagca cagctttgcc catcatttga 
               
               
                   
               
               
                 2101 
                 agagtcagaa gctactcctt caccagtttt gcctgacatt gttatggaag caccattgaa 
               
               
                   
               
               
                 2161 
                 ttctgcagtt cctagtgctg gtgcttccgt gatacagccc agctcatcac cattagaagc 
               
               
                   
               
               
                 2221 
                 ttcttcagtt aattatgaaa gcataaaaca tgagcctgaa aaccccccac catatgaaga 
               
               
                   
               
               
                 2281 
                 ggccatgagt gtatcactaa aaaaagtatc aggaataaag gaagaaatta aagagcctga 
               
               
                   
               
               
                 2341 
                 aaatattaat gcagctcttc aagaaacaga agctccttat atatctattg catgtgattt 
               
               
                   
               
               
                 2401 
                 aattaaagaa acaaagcttt ctgctgaacc agctccggat ttctctgatt attcagaaat 
               
               
                   
               
               
                 2461 
                 ggcaaaagtt gaacagccag tgcctgatca ttctgagcta gttgaagatt cctcacctga 
               
               
                   
               
               
                 2521 
                 ttctgaacca gttgacttat ttagtgatga ttcaatacct gacgttccac aaaaacaaga 
               
               
                   
               
               
                 2581 
                 tgaaactgtg atgcttgtga aagaaagtct cactgagact tcatttgagt caatgataga 
               
               
                   
               
               
                 2641 
                 atatgaaaat aaggaaaaac tcagtgcttt gccacctgag ggaggaaagc catatttgga 
               
               
                   
               
               
                 2701 
                 atcttttaag ctcagtttag ataacacaaa agataccctg ttacctgatg aagtttcaac 
               
               
                   
               
               
                 2761 
                 attgagcaaa aaggagaaaa ttcctttgca gatggaggag ctcagtactg cagtttattc 
               
               
                   
               
               
                 2821 
                 aaatgatgac ttatttattt ctaaggaagc acagataaga gaaactgaaa cgttttcaga 
               
               
                   
               
               
                 2881 
                 ttcatctcca attgaaatta tagatgagtt ccctacattg atcagttcta aaactgattc 
               
               
                   
               
               
                 2941 
                 attttctaaa ttagccaggg aatatactga cctagaagta tcccacaaaa gtgaaattgc 
               
               
                   
               
               
                 3001 
                 taatgccccg gatggagctg ggtcattgcc ttgcacagaa ttgccccatg acctttcttt 
               
               
                   
               
               
                 3061 
                 gaagaacata caacccaaag ttgaagagaa aatcagtttc tcagatgact tttctaaaaa 
               
               
                   
               
               
                 3121 
                 tgggtctgct acatcaaagg tgctcttatt gcctccagat gtttctgctt tggccactca 
               
               
                   
               
               
                 3181 
                 agcagagata gagagcatag ttaaacccaa agttcttgtg aaagaagctg agaaaaaact 
               
               
                   
               
               
                 3241 
                 tccttccgat acagaaaaag aggacagatc accatctgct atattttcag cagagctgag 
               
               
                   
               
               
                 3301 
                 taaaacttca gttgttgacc tcctgtactg gagagacatt aagaagactg gagtggtgtt 
               
               
                   
               
               
                 3361 
                 tggtgccagc ctattcctgc tgctttcatt gacagtattc agcattgtga gcgtaacagc 
               
               
                   
               
               
                 3421 
                 ctacattgcc ttggccctgc tctctgtgac catcagcttt aggatataca agggtgtgat 
               
               
                   
               
               
                 3481 
                 ccaagctatc cagaaatcag atgaaggcca cccattcagg gcatatctgg aatctgaagt 
               
               
                   
               
               
                 3541 
                 tgctatatct gaggagttgg ttcagaagta cagtaattct gctcttggtc atgtgaactg 
               
               
                   
               
               
                 3601 
                 cacgataaag gaactcaggc gcctcttctt agttgatgat ttagttgatt ctctgaagtt 
               
               
                   
               
               
                 3661 
                 tgcagtgttg atgtgggtat ttacctatgt tggtgccttg tttaatggtc tgacactact 
               
               
                   
               
               
                 3721 
                 gattttggct ctcatttcac tcttcagtgt tcctgttatt tatgaacggc atcaggcaca 
               
               
                   
               
               
                 3781 
                 gatagatcat tatctaggac ttgcaaataa gaatgttaaa gatgctatgg ctaaaatcca 
               
               
                   
               
               
                 3841 
                 agcaaaaatc cctggattga agcgcaaagc tgaatgaaaa cgcccaaaat aattagtagg 
               
               
                   
               
               
                 3901 
                 agttcatctt taaaggggat attcatttga ttatacgggg gagggtcagg gaagaacgaa 
               
               
                   
               
               
                 3961 
                 ccttgacgtt gcagtgcagt ttcacagatc gttgttagat ctttattttt agccatgcac 
               
               
                   
               
               
                 4021 
                 tgttgtgagg aaaaattacc tgtcttgact gccatgtgtt catcatctta agtattgtaa 
               
               
                   
               
               
                 4081 
                 gctgctatgt atggatttaa accgtaatca tatctttttc ctatctatct gaggcactgg 
               
               
                   
               
               
                 4141 
                 tggaataaaa aacctgtata ttttactttg ttgcagatag tcttgccgca tcttggcaag 
               
               
                   
               
               
                 4201 
                 ttgcagagat ggtggagcta gaaaaaaaaa aaaaaaagcc cttttcagtt tgtgcactgt 
               
               
                   
               
               
                 4261 
                 gtatggtccg tgtagattga tgcagatttt ctgaaatgaa atgtttgttt agacgagatc 
               
               
                   
               
               
                 4321 
                 ataccggtaa agcaggaatg acaaagcttg cttttctggt atgttctagg tgtattgtga 
               
               
                   
               
               
                 4381 
                 cttttactgt tatattaatt gccaatataa gtaaatatag attatatatg tatagtgttt 
               
               
                   
               
               
                 4441 
                 cacaaagctt agacctttac cttccagcca ccccacagtg cttgatattt cagagtcagt 
               
               
                   
               
               
                 4501 
                 cattggttat acatgtgtag ttccaaagca cataagctag aagaagaaat atttctagga 
               
               
                   
               
               
                 4561 
                 gcactaccat ctgttttcaa catgaaatgc cacacacata gaactccaac atcaatttca 
               
               
                   
               
               
                 4621 
                 ttgcacagac tgactgtagt taattttgtc acagaatcta tggactgaat ctaatgcttc 
               
               
                   
               
               
                 4681 
                 caaaaatgtt gtttgtttgc aaatatcaaa cattgttatg caagaaatta ttaattacaa 
               
               
                   
               
               
                 4741 
                 aatgaagatt tataccattg tggtttaagc tgtactgaac taaatctgtg gaatgcattg 
               
               
                   
               
               
                 4801 
                 tgaactgtaa aagcaaagta tcaataaagc ttatagactt aaaaaaaaaa aaaaaaaaaa 
               
               
                   
               
               
                 4861 
                 aaaaaaaaaa a 
               
            
           
         
       
     
     By “GFAP” (or Glial fibrillary acidic protein) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. P14136. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 45) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 merrritsaa rrsyvssgem mvgglapgrr lgpgtrlsla rmppplptrv dfslagalna 
                   
               
               
                   
               
               
                 61 
                 gfketraser aemmelndrf asyiekvrfl eqqnkalaae lnqlrakept kladvyqael 
               
               
                   
               
               
                 121 
                 relrlrldql tansarleve rdnlaqdlat vrqklqdetn lrleaennla ayrqeadeat 
               
               
                   
               
               
                 181 
                 larldlerki esleeeirfl rkiheeevre lqeqlarqqv hveldvakpd ltaalkeirt 
               
               
                   
               
               
                 241 
                 qyeamassnm heaeewyrsk fadltdaaar naellrqakh eandyrrqlq sltcdleslr 
               
               
                   
               
               
                 301 
                 gtneslerqm reqeerhvre aasyqealar leeegqslkd emarhlqeyq dllnvklald 
               
               
                   
               
               
                 361 
                 ieiatyrkll egeenritip vqtfsnlqir etsldtksvs eghlkrnivv ktvemrdgev 
               
               
                   
               
               
                 421 
                 ikeskqehkd vm 
               
            
           
         
       
     
     By “GFAP nucleic acid molecule” (or Glial fibrillary acidic protein) is meant a polynucleotide encoding an GFAP polypeptide. An exemplary GFAP nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. NM_002055. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 46) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 atcgccagtc tagcccactc cttcataaag ccctcgcatc ccaggagcga gcagagccag 
                   
               
               
                   
               
               
                 61 
                 agcaggatgg agaggagacg catcacctcc gctgctcgcc gctcctacgt ctcctcaggg 
               
               
                   
               
               
                 121 
                 gagatgatgg tggggggcct ggctcctggc cgccgtctgg gtcctggcac ccgcctctcc 
               
               
                   
               
               
                 181 
                 ctggctcgaa tgccccctcc actcccgacc cgggtggatt tctccctggc tggggcactc 
               
               
                   
               
               
                 241 
                 aatgctggct tcaaggagac ccgggccagt gagcgggcag agatgatgga gctcaatgac 
               
               
                   
               
               
                 301 
                 cgctttgcca gctacatcga gaaggttcgc ttcctggaac agcaaaacaa ggcgctggct 
               
               
                   
               
               
                 361 
                 gctgagctga accagctgcg ggccaaggag cccaccaagc tggcagacgt ctaccaggct 
               
               
                   
               
               
                 421 
                 gagctgcgag agctgcggct gcggctcgat caactcaccg ccaacagcgc ccggctggag 
               
               
                   
               
               
                 481 
                 gttgagaggg acaatctggc acaggacctg gccactgtga ggcagaagct ccaggatgaa 
               
               
                   
               
               
                 541 
                 accaacctga ggctggaagc cgagaacaac ctggctgcct atagacagga agcagatgaa 
               
               
                   
               
               
                 601 
                 gccaccctgg cccgtctgga tctggagagg aagattgagt cgctggagga ggagatccgg 
               
               
                   
               
               
                 661 
                 ttcttgagga agatccacga ggaggaggtt cgggaactcc aggagcagct ggcccgacag 
               
               
                   
               
               
                 721 
                 caggtccatg tggagcttga cgtggccaag ccagacctca ccgcagccct gaaagagatc 
               
               
                   
               
               
                 781 
                 cgcacgcagt atgaggcaat ggcgtccagc aacatgcatg aagccgaaga gtggtaccgc 
               
               
                   
               
               
                 841 
                 tccaagtttg cagacctgac agacgctgct gcccgcaacg cggagctgct ccgccaggcc 
               
               
                   
               
               
                 901 
                 aagcacgaag ccaacgacta ccggcgccag ttgcagtcct tgacctgcga cctggagtct 
               
               
                   
               
               
                 961 
                 ctgcgcggca cgaacgagtc cctggagagg cagatgcgcg agcaggagga gcggcacgtg 
               
               
                   
               
               
                 1021 
                 cgggaggcgg ccagttatca ggaggcgctg gcgcggctgg aggaagaggg gcagagcctc 
               
               
                   
               
               
                 1081 
                 aaggacgaga tggcccgcca cttgcaggag taccaggacc tgctcaatgt caagctggcc 
               
               
                   
               
               
                 1141 
                 ctggacatcg agatcgccac ctacaggaag ctgctagagg gcgaggagaa ccggatcacc 
               
               
                   
               
               
                 1201 
                 attcccgtgc agaccttctc caacctgcag attcgagaaa ccagcctgga caccaagtct 
               
               
                   
               
               
                 1261 
                 gtgtcagaag gccacctcaa gaggaacatc gtggtgaaga ccgtggagat gcgggatgga 
               
               
                   
               
               
                 1321 
                 gaggtcatta aggagtccaa gcaggagcac aaggatgtga tgtgaggcag gacccacctg 
               
               
                   
               
               
                 1381 
                 gtggcctctg ccccgtctca tgaggggccc gagcagaagc aggatagttg ctccgcctct 
               
               
                   
               
               
                 1441 
                 gctggcacat ttccccagac ctgagctccc caccacccca gctgctcccc tccctcctct 
               
               
                   
               
               
                 1501 
                 gtccctaggt cagcttgctg ccctaggctc cgtcagtatc aggcctgcca gacggcaccc 
               
               
                   
               
               
                 1561 
                 acccagcacc cagcaactcc aactaacaag aaactcaccc ccaaggggca gtctggaggg 
               
               
                   
               
               
                 1621 
                 gcatggccag cagcttgcgt tagaatgagg aggaaggaga gaaggggagg agggcggggg 
               
               
                   
               
               
                 1681 
                 gcacctacta catcgccctc cacatccctg attcctgttg ttatggaaac tgttgccaga 
               
               
                   
               
               
                 1741 
                 gatggaggtt ctctcggagt atctgggaac tgtgcctttg agtttcctca ggctgctgga 
               
               
                   
               
               
                 1801 
                 ggaaaactga gactcagaca ggaaagggaa ggccccacag acaaggtagc cctggccaga 
               
               
                   
               
               
                 1861 
                 ggcttgtttt gtcttttggt ttttatgagg tgggatatcc ctatgctgcc taggctgacc 
               
               
                   
               
               
                 1921 
                 ttgaactcct gggctcaagc agtctaccca cctcagcctc ctgtgtagct gggattatag 
               
               
                   
               
               
                 1981 
                 attggagcca ccatgcccag ctcagagggt tgttctccta gactgaccct gatcagtcta 
               
               
                   
               
               
                 2041 
                 agatgggtgg ggacgtcctg ccacctgggg cagtcacctg cccagatccc agaaggacct 
               
               
                   
               
               
                 2101 
                 cctgagcgat gactcaagtg tctcagtcca cctgagctgc catccaggga tgccatctgt 
               
               
                   
               
               
                 2161 
                 gggcacgctg tgggcaggtg ggagcttgat tctcagcact tgggggatct gttgtgtacg 
               
               
                   
               
               
                 2221 
                 tggagaggga tgaggtgctg ggagggatag aggggggctg cctggccccc agctgtgggt 
               
               
                   
               
               
                 2281 
                 acagagaggt caagcccagg aggactgccc cgtgcagact ggaggggacg ctggtagaga 
               
               
                   
               
               
                 2341 
                 tggaggagga ggcaattggg atggcgctag gcatacaagt aggggttgtg ggtgaccagt 
               
               
                   
               
               
                 2401 
                 tgcacttggc ctctggattg tgggaattaa ggaagtgact catcctcttg aagatgctga 
               
               
                   
               
               
                 2461 
                 aacaggagag aaaggggatg tatccatggg ggcagggcat gactttgtcc catttctaaa 
               
               
                   
               
               
                 2521 
                 ggcctcttcc ttgctgtgtc ataccaggcc gccccagcct ctgagcccct gggactgctg 
               
               
                   
               
               
                 2581 
                 cttcttaacc ccagtaagcc actgccacac gtctgaccct ctccacccca tagtgaccgg 
               
               
                   
               
               
                 2641 
                 ctgcttttcc ctaagccaag ggcctcttgc ggtcccttct tactcacaca caaaatgtac 
               
               
                   
               
               
                 2701 
                 ccagtattct aggtagtgcc ctattttaca attgtaaaac tgaggcacga gcaaagtgaa 
               
               
                   
               
               
                 2761 
                 gacactggct catattcctg cagcctggag gccgggtgct cagggctgac acgtccaccc 
               
               
                   
               
               
                 2821 
                 cagtgcaccc actctgcttt gactgagcag actggtgagc agactggtgg gatctgtgcc 
               
               
                   
               
               
                 2881 
                 cagagatggg actgggaggg cccacttcag ggttctcctc tcccctctaa ggccgaagaa 
               
               
                   
               
               
                 2941 
                 gggtccttcc ctctccccaa gacttggtgt cctttccctc cactccttcc tgccacctgc 
               
               
                   
               
               
                 3001 
                 tgctgctgct gctgctaatc ttcagggcac tgctgctgcc tttagtcgct gaggaaaaat 
               
               
                   
               
               
                 3061 
                 aaagacaaat gctgcgccct tccccaaaaa aaaaaaa 
               
            
           
         
       
     
     By “s110b” (or S-100 protein beta chain; S-100 protein subunit beta; S100 calcium-binding protein B) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. P04271. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 47) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 mselekamva lidvfhqysg regdkhklkk selkelinne lshfleeike qevvdkvmet 
                   
               
               
                   
               
               
                 61 
                 ldndgdgecd fqefmafvam vttacheffe he 
               
            
           
         
       
     
     By “s100b nucleic acid molecule” (or S-100 protein beta chain; S-100 protein subunit beta; S100 calcium-binding protein B) is meant a polynucleotide encoding an s100b polypeptide. An exemplary s100b nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. NM_006272. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 48) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 gggcagaggg aataagaggc tgcctctgcc caccagtcct gccgcccagg acccgcagca 
                   
               
               
                   
               
               
                 61 
                 gagacgacgc ctgcagcaag gagaccagga aggggtgaga caaggaagag gatgtctgag 
               
               
                   
               
               
                 121 
                 ctggagaagg ccatggtggc cctcatcgac gttttccacc aatattctgg aagggaggga 
               
               
                   
               
               
                 181 
                 gacaagcaca agctgaagaa atccgaactg aaggagctca tcaacaatga gctttcccat 
               
               
                   
               
               
                 241 
                 ttcttagagg aaatcaaaga gcaggaggtt gtggacaaag tcatggaaac actggacaat 
               
               
                   
               
               
                 301 
                 gatggagacg gcgaatgtga cttccaggaa ttcatggcct ttgttgccat ggttactact 
               
               
                   
               
               
                 361 
                 gcctgccacg agttctttga acatgagtga gattagaaag cagccaaacc tttcctgtaa 
               
               
                   
               
               
                 421 
                 cagagacggt catgcaagaa agcagacagc aagggcttgc agcctagtag gagctgagct 
               
               
                   
               
               
                 481 
                 ttccagccgt gttgtagcta attaggaagc ttgatttgct ttgtgattga aaaattgaaa 
               
               
                   
               
               
                 541 
                 acctctttcc aaaggctgtt ttaacggcct gcatcattct ttctgctata ttaggcctgt 
               
               
                   
               
               
                 601 
                 gtgtaagctg actggcccca gggactcttg ttaacagtaa cttaggagtc aggtctcagt 
               
               
                   
               
               
                 661 
                 gataaagcgt gcaccgtgca gcccgccatg gccgtgtaga ccctaacccg gagggaaccc 
               
               
                   
               
               
                 721 
                 tgactacaga aattaccccg gggcaccctt aaaacttcca ctacctttaa aaaacaaagc 
               
               
                   
               
               
                 781 
                 cttatccagc attatttgaa aacactgctg ttctttaaat gcgttcctca tccatgcaga 
               
               
                   
               
               
                 841 
                 taacagctgg ttggccggtg tggccctgca agggcgtggt ggcttcggcc tgcttcccgg 
               
               
                   
               
               
                 901 
                 gatgcgcctg atcaccaggt gaacgctcag cgctggcagc gctcctggaa aaagcaactc 
               
               
                   
               
               
                 961 
                 catcagaact cgcaatccga gccagctctg ggggctccag cgtggcctcc gtgacccatg 
               
               
                   
               
               
                 1021 
                 cgattcaagt cgcggctgca ggatccttgc ctccaacgtg cctccagcac atgcggcttc 
               
               
                   
               
               
                 1081 
                 cgagggcact accgggggct ctgagccacc gcgagggcct gcgttcaata aaaag 
               
            
           
         
       
     
     By “PAX6 polypeptide” (or paired box protein PAX6) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. AAK95849.1. 
     
       
         
           
               
            
               
                 (SEQ ID NO: 49) 
               
               
                 MQNSHSGVNQLGGVFVNGRPLPDSTRQKIVELAHSGARPCDISRILQVSN 
               
               
                   
               
               
                 GCVSKILGRYYETGSIRPRAIGGSKPRVATPEVVSKIAQYKRECPSIFAW 
               
               
                   
               
               
                 EIRDRLLSEGVCTNDNIPSVSSINRVLRNLASEKQQMGADGMYDKLRMLN 
               
               
                   
               
               
                 GQTGSWGTRPGWYPGTSVPGQPTQDGCQQQEGGGENTNSISSNGEDSDEA 
               
               
                   
               
               
                 QMRLQLKRKLQRNRTSFTQEQIEALEKEFERTHYPDVFARERLAAKIDLP 
               
               
                   
               
               
                 EARIQVWFSNRRAKWRREEKLRNQRRQASNTPSHIPISSSFSTSVYQPIP 
               
               
                   
               
               
                 QPTTPVSSFTSGSMLGRTDTALTNTYSALPPMPSFTMANNLPMQPPVPSQ 
               
               
                   
               
               
                 TSSYSCMLPTSPSVNGRSYDTYTPPHMQTHMNSQPMGTSGTTSTGLISPG 
               
               
                   
               
               
                 VSVPVQVPGSEPDMSQYWPRLQ 
               
            
           
         
       
     
     By “PAX6 polynucleotide” (or paired box protein PAX6) is meant a polynucleotide encoding an PAX6 polypeptide. An exemplary PAX6 nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. AY047583. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 50) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 agggggaaga ctttaactag gggcgcgcag atgtgtgagg ccttttattg tgagagtgga 
                   
               
               
                   
               
               
                 61 
                 cagacatccg agatttcaga gccccatatt cgagccccgt ggaatcccgc ggcccccagc 
               
               
                   
               
               
                 121 
                 cagagccagc atgcagaaca gtcacagcgg agtgaatcag ctcggtggtg tctttgtcaa 
               
               
                   
               
               
                 181 
                 cgggcggcca ctgccggact ccacccggca gaagattgta gagctagctc acagcggggc 
               
               
                   
               
               
                 241 
                 ccggccgtgc gacatttccc gaattctgca ggtgtccaac ggatgtgtga gtaaaattct 
               
               
                   
               
               
                 301 
                 gggcaggtat tacgagactg gctccatcag acccagggca atcggtggta gtaaaccgag 
               
               
                   
               
               
                 361 
                 agtagcgact ccagaagttg taagcaaaat agcccagtat aagcgggagt gcccgtccat 
               
               
                   
               
               
                 421 
                 ctttgcttgg gaaatccgag acagattact gtccgagggg gtctgtacca acgataacat 
               
               
                   
               
               
                 481 
                 accaagcgtg tcatcaataa acagagttct tcgcaacctg gctagcgaaa agcaacagat 
               
               
                   
               
               
                 541 
                 gggcgcagac ggcatgtatg ataaactaag gatgttgaac gggcagaccg gaagctgggg 
               
               
                   
               
               
                 601 
                 cacccgccct ggttggtatc cggggacttc ggtgccaggg caacctacgc aagatggctg 
               
               
                   
               
               
                 661 
                 ccagcaacag gaaggagggg gagagaatac caactccatc agttccaacg gagaagattc 
               
               
                   
               
               
                 721 
                 agatgaggct caaatgcgac ttcagctgaa gcggaagctg caaagaaata gaacatcctt 
               
               
                   
               
               
                 781 
                 tacccaagag caaattgagg ccctggagaa agagtttgag agaacccatt atccagatgt 
               
               
                   
               
               
                 841 
                 gtttgcccga gaaagactag cagccaaaat agatctacct gaagcaagaa tacaggtatg 
               
               
                   
               
               
                 901 
                 gttttctaat cgaagggcca aatggagaag agaagaaaaa ctgaggaatc agagaagaca 
               
               
                   
               
               
                 961 
                 ggccagcaac acacctagtc atattcctat cagcagtagt ttcagcacca gtgtctacca 
               
               
                   
               
               
                 1021 
                 accaattcca caacccacca caccggtttc ctccttcaca tctggctcca tgttgggccg 
               
               
                   
               
               
                 1081 
                 aacagacaca gccctcacaa acacctacag cgctctgccg cctatgccca gcttcaccat 
               
               
                   
               
               
                 1141 
                 ggcaaataac ctgcctatgc aacccccagt ccccagccag acctcctcat actcctgcat 
               
               
                   
               
               
                 1201 
                 gctgcccacc agcccttcgg tgaatgggcg gagttatgat acctacaccc ccccacatat 
               
               
                   
               
               
                 1261 
                 gcagacacac atgaacagtc agccaatggg cacctcgggc accacttcaa caggactcat 
               
               
                   
               
               
                 1321 
                 ttcccctggt gtgtcagttc cagttcaagt tcccggaagt gaacctgata tgtctcaata 
               
               
                   
               
               
                 1381 
                 ctggccaaga ttacagtaa 
               
            
           
         
       
     
     By “Nestin polypeptide” is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. NP_006608.1. 
     
       
         
           
               
            
               
                 (SEQ ID NO: 51) 
               
               
                 MEGCMGEESFQMWELNRRLEAYLARVKALEEQNELLSAELGGLRAQSADT 
               
               
                   
               
               
                 SWRAHADDELAALRALVDQRWREKHAAEVARDNLAEELEGVAGRCQQLRL 
               
               
                   
               
               
                 ARERTTEEVARNRRAVEAEKCARAWLSSQVAELERELEALRVAHEEERVG 
               
               
                   
               
               
                 LNAQAACAPRCPAPPRGPPAPAPEVEELARRLGEAWRGAVRGYQERVAHM 
               
               
                   
               
               
                 ETSLGQARERLGRAVQGAREGRLELQQLQAERGGLLERRAALEQRLEGRW 
               
               
                   
               
               
                 QERLRATEKFQLAVEALEQEKQGLQSQIAQVLEGRQQLAHLKMSLSLEVA 
               
               
                   
               
               
                 TYRTLLEAENSRLQTPGGGSKTSLSFQDPKLELQFPRTPEGRRLGSLLPV 
               
               
                   
               
               
                 LSPTSLPSPLPATLETPVPAFLKNQEFLQARTPTLASTPIPPTPQAPSPA 
               
               
                   
               
               
                 VDAEIRAQDAPLSLLQTQGGRKQAPEPLRAEARVAIPASVLPGPEEPGGQ 
               
               
                   
               
               
                 RQEASTGQSPEDHASLAPPLSPDHSSLEAKDGESGGSRVFSICRGEGEGQ 
               
               
                   
               
               
                 IWGLVEKETAIEGKVVSSLQQEIWEEEDLNRKEIQDSQVPLEKETLKSLG 
               
               
                   
               
               
                 EEIQESLKTLENQSHETLERENQECPRSLEEDLETLKSLEKENKELLKDV 
               
               
                   
               
               
                 EVVRPLEKEAVGQLKPTGKEDTQTLQSLQKENQELMKSLEGNLETFLFPG 
               
               
                   
               
               
                 TENQELVSSLQENLESLTALEKENQEPLRSPEVGDEEALRPLTKENQEPL 
               
               
                   
               
               
                 RSLEDENKEAFRSLEKENQEPLKTLEEEDQSIVRPLETENHKSLRSLEEQ 
               
               
                   
               
               
                 DQETLRTLEKETQQRRRSLGEQDQMTLRPPEKVDLEPLKSLDQEIARPLE 
               
               
                   
               
               
                 NENQEFLKSLKEESVEAVKSLETEILESLKSAGQENLETLKSPETQAPLW 
               
               
                   
               
               
                 TPEEINQGAMNPLEKEIQEPLESVEVNQETFRLLEEENQESLRSLGAWNL 
               
               
                   
               
               
                 ENLRSPEEVDKESQRNLEEEENLGKGEYQESLRSLEEEGQELPQSADVQR 
               
               
                   
               
               
                 WEDTVEKDQELAQESPPGMAGVENEDEAELNLREQDGFTGKEEVVEQGEL 
               
               
                   
               
               
                 NATEEVWIPGEGHPESPEPKEQRGLVEGASVKGGAEGLQDPEGQSQQVGA 
               
               
                   
               
               
                 PGLQAPQGLPEAIEPLVEDDVAPGGDQASPEVMLGSEPAMGESAAGAEPG 
               
               
                   
               
               
                 PGQGVGGLGDPGHLTREEVMEPPLEEESLEAKRVQGLEGPRKDLEEAGGL 
               
               
                   
               
               
                 GTEFSELPGKSRDPWEPPREGREESEAEAPRGAEEAFPAETLGHTGSDAP 
               
               
                   
               
               
                 SPWPLGSEEAEEDVPPVLVSPSPTYTPILEDAPGPQPQAEGSQEASWGVQ 
               
               
                   
               
               
                 GRAEALGKVESEQEELGSGEIPEGPQEEGEESREESEEDELGETLPDSTP 
               
               
                   
               
               
                 LGFYLRSPTSPRWDPTGEQRPPPQGETGKEGWDPAVLASEGLEAPPSEKE 
               
               
                   
               
               
                 EGEEGEEECGRDSDLSEEFEDLGTEAPFLPGVPGEVAEPLGQVPQLLLDP 
               
               
                   
               
               
                 AAWDRDGESDGFADEEESGEEGEEDQEEGREPGAGRWGPGSSVGSLQALS 
               
               
                   
               
               
                 SSQRGEFLESDSVSVSVPWDDSLRGAVAGAPKTALETESQDSAEPSGSEE 
               
               
                   
               
               
                 ESDPVSLEREDKVPGPLEIPSGMEDAGPGADIIGVNGQGPNLEGKSQHVN 
               
               
                   
               
               
                 GGVMNGLEQSEEVGQGMPLVSEGDRGSPFQEEEGSALKTSWAGAPVHLGQ 
               
               
                   
               
               
                 GQFLKFTQREGDRESWSSGED 
               
            
           
         
       
     
     By “Nestin polynucleotide” is meant a polynucleotide encoding an Nestin polypeptide. An exemplary Nestin nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. NM_006617. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 52) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 gctactccca ccccgccccg ccccgtcatt gtccccgtcg gtctcttttc tcttccgtcc 
                   
               
               
                   
               
               
                 61 
                 taaaagctct gcgagccgct cccttctccc ggtgccccgc gtctgtccat cctcagtggg 
               
               
                   
               
               
                 121 
                 tcagacgagc aggatggagg gctgcatggg ggaggagtcg tttcagatgt gggagctcaa 
               
               
                   
               
               
                 181 
                 tcggcgcctg gaggcctacc tggcccgggt caaggcgctg gaggagcaga atgagctgct 
               
               
                   
               
               
                 241 
                 cagcgcggag ctcggggggc tccgggcaca atccgcggac acctcctggc gggcgcatgc 
               
               
                   
               
               
                 301 
                 cgacgacgag ctggcggccc tgcgggccct cgttgaccaa cgctggcggg agaagcacgc 
               
               
                   
               
               
                 361 
                 ggccgaggtg gcgcgcgaca acctggctga agagctggag ggcgtggcag gccgatgcca 
               
               
                   
               
               
                 421 
                 gcagctgcgg ctggcccggg agcggacgac ggaggaggta gcccgcaacc ggcgcgccgt 
               
               
                   
               
               
                 481 
                 cgaggcagag aaatgcgccc gggcctggct gagtagccag gtggcagagc tggagcgcga 
               
               
                   
               
               
                 541 
                 gctagaggct ctacgcgtgg cgcacgagga ggagcgcgtc ggcctgaacg cgcaggctgc 
               
               
                   
               
               
                 601 
                 ctgtgccccc cgctgccccg cgccgccccg cgggcctccc gcgccggccc cggaggtaga 
               
               
                   
               
               
                 661 
                 ggagctggca aggcgactgg gcgaggcgtg gcgcggggca gtgcgcggct accaggagcg 
               
               
                   
               
               
                 721 
                 cgtggcacac atggagacgt cgctgggcca ggcccgcgag cggctgggcc gggcggtgca 
               
               
                   
               
               
                 781 
                 gggtgcccgc gagggccgcc tggagctgca gcagctccag gctgagcgcg gaggcctcct 
               
               
                   
               
               
                 841 
                 ggagcgcagg gcagcgttgg aacagaggtt ggagggccgc tggcaggagc ggctgcgggc 
               
               
                   
               
               
                 901 
                 tactgaaaag ttccagctgg ctgtggaggc cctggagcag gagaaacagg gcctacagag 
               
               
                   
               
               
                 961 
                 ccagatcgct caggtcctgg aaggtcggca gcagctggcg cacctcaaga tgtccctcag 
               
               
                   
               
               
                 1021 
                 cctggaggtg gccacgtaca ggaccctcct ggaggctgag aactcccggc tgcaaacacc 
               
               
                   
               
               
                 1081 
                 tggcggtggc tccaagactt ccctcagctt tcaggacccc aagctggagc tgcaattccc 
               
               
                   
               
               
                 1141 
                 taggacccca gagggccggc gtcttggatc tttgctccca gtcctgagcc caacttccct 
               
               
                   
               
               
                 1201 
                 cccctcaccc ttgcctgcta cccttgagac acctgtgcca gcctttctta agaaccaaga 
               
               
                   
               
               
                 1261 
                 attcctccag gcccgtaccc ctaccttggc cagcaccccc atccccccca cacctcaggc 
               
               
                   
               
               
                 1321 
                 accctctcct gctgtagatg cagagatcag agcccaggat gctcctctct ctctgctcca 
               
               
                   
               
               
                 1381 
                 gacacagggt gggaggaaac aggctccaga gcccctgcgg gctgaagcca gggtggccat 
               
               
                   
               
               
                 1441 
                 tcctgccagc gtcctgcctg gaccagagga gcctgggggc cagcggcaag aggccagtac 
               
               
                   
               
               
                 1501 
                 aggccagtcc ccagaggacc atgcctcctt ggcaccaccc ctcagccctg accactccag 
               
               
                   
               
               
                 1561 
                 tttagaggct aaggatggag aatccggtgg gtctagagtg ttcagcatat gccgagggga 
               
               
                   
               
               
                 1621 
                 aggtgaaggg caaatctggg ggttggtaga gaaagaaaca gccatagagg gcaaagtggt 
               
               
                   
               
               
                 1681 
                 aagcagcttg cagcaggaaa tatgggaaga agaggatcta aacaggaagg aaatccagga 
               
               
                   
               
               
                 1741 
                 ctcccaggtt cctttggaaa aagaaaccct gaagtctctg ggagaggaga ttcaagagtc 
               
               
                   
               
               
                 1801 
                 actgaagact ctggaaaacc agagccatga gacactagaa agggagaatc aagaatgtcc 
               
               
                   
               
               
                 1861 
                 gaggtcttta gaagaagact tagaaacact aaaaagtcta gaaaaggaaa ataaagagct 
               
               
                   
               
               
                 1921 
                 attaaaggat gtggaggtag tgagacctct agaaaaagag gctgtaggcc aacttaagcc 
               
               
                   
               
               
                 1981 
                 tacaggaaaa gaggacacac agacattgca atccctgcaa aaggagaatc aagaactaat 
               
               
                   
               
               
                 2041 
                 gaaatctctt gaaggtaatc tagagacatt tttatttcca ggaacggaaa atcaagaatt 
               
               
                   
               
               
                 2101 
                 agtaagttct ctgcaagaga acttagagtc attgacagct ctggaaaagg agaatcaaga 
               
               
                   
               
               
                 2161 
                 gccactgaga tctccagaag taggggatga ggaggcactg agacctctga caaaggagaa 
               
               
                   
               
               
                 2221 
                 tcaggaaccc ctgaggtctc ttgaagatga gaacaaagag gcctttagat ctctagaaaa 
               
               
                   
               
               
                 2281 
                 agagaaccag gagccactga agactctaga agaagaggac cagagtattg tgagacctct 
               
               
                   
               
               
                 2341 
                 agaaacagag aatcacaaat cactgaggtc tttagaagaa caggaccaag agacattgag 
               
               
                   
               
               
                 2401 
                 aactcttgaa aaagagactc aacagcgacg gaggtctcta ggggaacagg atcagatgac 
               
               
                   
               
               
                 2461 
                 attaagaccc ccagaaaaag tggatctaga accactgaag tctcttgacc aggagatagc 
               
               
                   
               
               
                 2521 
                 tagacctctt gaaaatgaga atcaagagtt cttaaagtca ctcaaagaag agagcgtaga 
               
               
                   
               
               
                 2581 
                 ggcagtaaaa tctttagaaa cagagatcct agaatcactg aagtctgcgg gacaagagaa 
               
               
                   
               
               
                 2641 
                 cctggaaaca ctgaaatctc cagaaactca agcaccactg tggactccag aagaaataaa 
               
               
                   
               
               
                 2701 
                 tcagggggca atgaatcctc tagaaaagga aattcaagaa ccactggagt ctgtggaagt 
               
               
                   
               
               
                 2761 
                 gaaccaagag acattcagac tcctggaaga ggagaatcag gaatcattga gatctctggg 
               
               
                   
               
               
                 2821 
                 agcatggaac ctggagaatt tgagatctcc agaggaggta gacaaggaaa gtcaaaggaa 
               
               
                   
               
               
                 2881 
                 tctggaagag gaagagaacc tgggaaaggg agagtaccaa gagtcactga ggtctctgga 
               
               
                   
               
               
                 2941 
                 ggaggaggga caggagctgc cgcagtctgc agatgtgcag aggtgggaag atacggtgga 
               
               
                   
               
               
                 3001 
                 gaaggaccaa gaactggctc aggaaagccc tcctgggatg gctggagtgg aaaatgagga 
               
               
                   
               
               
                 3061 
                 tgaggcagag ctgaatctga gggagcagga tggcttcact gggaaggagg aggtggtaga 
               
               
                   
               
               
                 3121 
                 gcagggagag ctgaatgcca cagaggaggt ctggatccca ggcgaggggc acccagagag 
               
               
                   
               
               
                 3181 
                 ccctgagccc aaagagcaga gaggcctggt tgagggagcc agtgtgaagg gaggggctga 
               
               
                   
               
               
                 3241 
                 gggcctccag gaccctgaag ggcaatcaca acaggtgggg gccccaggcc tccaggctcc 
               
               
                   
               
               
                 3301 
                 ccaggggctg ccagaggcga tagagcccct ggtggaagat gatgtggccc cagggggtga 
               
               
                   
               
               
                 3361 
                 ccaagcctcc ccagaggtca tgttggggtc agagcctgcc atgggtgagt ctgctgcggg 
               
               
                   
               
               
                 3421 
                 agctgagcca ggcccggggc agggggtggg agggctgggg gacccaggcc atctgaccag 
               
               
                   
               
               
                 3481 
                 ggaagaggtg atggaaccac ccctggaaga ggagagtttg gaggcaaaga gggttcaggg 
               
               
                   
               
               
                 3541 
                 cttggaaggg cctagaaagg acctagagga ggcaggtggt ctggggacag agttctccga 
               
               
                   
               
               
                 3601 
                 gctgcctggg aagagcagag acccttggga gcctcccagg gagggtaggg aggagtcaga 
               
               
                   
               
               
                 3661 
                 ggctgaggcc cccaggggag cagaggaggc gttccctgct gagaccctgg gccacactgg 
               
               
                   
               
               
                 3721 
                 aagtgatgcc ccttcacctt ggcctctggg gtcagaggaa gctgaggagg atgtaccacc 
               
               
                   
               
               
                 3781 
                 agtgctggtc tcccccagcc caacgtacac cccgatcctg gaagatgccc ctgggcctca 
               
               
                   
               
               
                 3841 
                 gcctcaggct gaagggagtc aggaggctag ctggggggtg caggggaggg ctgaagccct 
               
               
                   
               
               
                 3901 
                 ggggaaagta gagagcgagc aggaggagtt gggttctggg gagatccccg agggccccca 
               
               
                   
               
               
                 3961 
                 ggaggaaggg gaggagagca gagaagagag cgaggaggat gagctcgggg agacccttcc 
               
               
                   
               
               
                 4021 
                 agactccact cccctgggct tctacctcag gtcccccacc tcccccaggt gggaccccac 
               
               
                   
               
               
                 4081 
                 tggagagcag aggccacccc ctcaagggga gactggaaag gagggctggg atcctgctgt 
               
               
                   
               
               
                 4141 
                 cctggcttcc gagggccttg aggccccacc ctcagaaaag gaggaggggg aggagggaga 
               
               
                   
               
               
                 4201 
                 agaggagtgt ggccgtgact ctgacctgtc agaagaattt gaggacctgg ggactgaggc 
               
               
                   
               
               
                 4261 
                 accttttctt cctggggtcc ctggggaggt ggcagaacct ctgggccagg tgccccagct 
               
               
                   
               
               
                 4321 
                 gctactggat cctgcagcct gggatcgaga tggggagtcc gatgggtttg cagatgagga 
               
               
                   
               
               
                 4381 
                 agaaagtggg gaggagggag aggaggatca ggaggagggg agggagccag gggctgggcg 
               
               
                   
               
               
                 4441 
                 gtgggggcca gggtcttctg ttggcagcct ccaggccctg agtagctccc agagagggga 
               
               
                   
               
               
                 4501 
                 attcctggag tctgattctg tgagtgtcag tgtcccctgg gatgacagct tgaggggtgc 
               
               
                   
               
               
                 4561 
                 agtggctggt gcccccaaga ctgccctgga aacggagtcc caggacagtg ctgagccttc 
               
               
                   
               
               
                 4621 
                 tggctcagag gaagagtctg accctgtttc cttggagagg gaggacaaag tccctggccc 
               
               
                   
               
               
                 4681 
                 tctagagatc cccagtggga tggaggatgc aggcccaggg gcagacatca ttggtgttaa 
               
               
                   
               
               
                 4741 
                 tggccagggt cccaacttgg aggggaagtc acagcatgtg aatgggggag tgatgaacgg 
               
               
                   
               
               
                 4801 
                 gctggagcag tctgaggaag tggggcaagg aatgccgcta gtctctgagg gagaccgagg 
               
               
                   
               
               
                 4861 
                 gagccccttt caggaggagg aggggagtgc tctgaagacc tcttgggcag gggctcctgt 
               
               
                   
               
               
                 4921 
                 tcacctgggc cagggtcagt tcctgaagtt cactcagagg gaaggagata gagagtcctg 
               
               
                   
               
               
                 4981 
                 gtcctcaggg gaggactagg aaaagaccat ctgcccggca ctggggactt aggggtgcgg 
               
               
                   
               
               
                 5041 
                 ggaggggaag gacgcctcca agcccgctcc ctgctcagga gcagcactct taacttacga 
               
               
                   
               
               
                 5101 
                 tctcttgaca tatggtttct ggctgagagg cctggcccgc taaggtgaaa aggggtgtgg 
               
               
                   
               
               
                 5161 
                 caaaggagcc tactccaaga atggaggctg taggaatata acctcccacc ctgcaaaggg 
               
               
                   
               
               
                 5221 
                 aatctcttgc ctgctccatc tcataggcta agtcagctga atcccgatag tactaggtcc 
               
               
                   
               
               
                 5281 
                 ccttccctcc gcatcccgtc agctggaaaa ggcctgtggc ccagaggctt ctccaaaggg 
               
               
                   
               
               
                 5341 
                 agggtgacat gctggctttt gtgcccaagc tcaccagccc tgcgccacct cactgcagta 
               
               
                   
               
               
                 5401 
                 gtgcaccatc tcactgcagt agcacgccct cctgggccgt ctggcctgtg gctaatggag 
               
               
                   
               
               
                 5461 
                 gtgacggcac tcccatgtgc tgactccccc catccctgcc acgctgtggc cctgcctggc 
               
               
                   
               
               
                 5521 
                 tagtccctgc ctgaataaag taatgcctcc gcttcaaaaa aaaaaaaaaa aaaaaaaaaa 
               
               
                   
               
               
                 5581 
                 aaaaaaaaaa a 
               
            
           
         
       
     
     By “LHX6 polypeptide” (or LIM homeobox 6) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. AAI03937.1. 
     
       
         
           
               
            
               
                 (SEQ ID NO: 53) 
               
               
                 MAQPGSGCKATTRCLEGTAPPAMAQSDAEALAGALDKDEGQASPCTPSTPS 
               
               
                   
               
               
                 VCSPPSAASSVPSAGKNICSSCGLEILDRYLLKVNNLIWHVRCLECSVCRT 
               
               
                   
               
               
                 SLRQQNSCYIKNKEIFCKMDYFSRFGTKCARCGRQIYASDWVRRARGNAYH 
               
               
                   
               
               
                 LACFACFSCKRQLSTGEEFGLVEEKVLCRIHYDTMIENLKRAAENGNGLTL 
               
               
                   
               
               
                 EGAVPSEQDSQPKPAKRARTSFTAEQLQVMQAQFAQDNNPDAQTLQKLADM 
               
               
                   
               
               
                 TGLSRRVIQVWFQNCRARHKKHTPQHPVPPSGAPPSRLPSALSDDIHYTPF 
               
               
                   
               
               
                 SSPERARMVTLHGYIESHPFSVLTLPALPHLPVGAPQLPLSR 
               
            
           
         
       
     
     By “LHX6 polynucleotide” (or LIM homeobox 6) is meant a polynucleotide encoding an LHX6 polypeptide. An exemplary LHX6 nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. BC103936. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 54) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 cccgccaccg accaggtgat ggcccagcca gggtccggct gcaaagcgac cacccgctgt 
                   
               
               
                   
               
               
                 61 
                 cttgaaggga ccgcgccgcc cgccatggct cagtctgacg ccgaggccct ggcaggagct 
               
               
                   
               
               
                 121 
                 ctggacaagg acgagggtca ggcctcccca tgtacgccca gcacgccatc tgtctgctca 
               
               
                   
               
               
                 181 
                 ccgccctctg ccgcctcctc cgtgccgtct gcaggcaaga acatctgctc cagctgcggc 
               
               
                   
               
               
                 241 
                 ctcgagatcc tggaccgata tctgctcaag gtcaacaacc tcatctggca cgtgcggtgc 
               
               
                   
               
               
                 301 
                 ctcgagtgct ccgtgtgtcg cacgtcgctg aggcagcaga acagctgcta catcaagaac 
               
               
                   
               
               
                 361 
                 aaggagatct tctgcaagat ggactacttc agccgattcg ggaccaagtg tgcccggtgc 
               
               
                   
               
               
                 421 
                 ggccgacaga tctacgccag cgactgggtg cggagagctc gcggcaacgc ctaccacctg 
               
               
                   
               
               
                 481 
                 gcctgcttcg cctgcttctc gtgcaagcgc cagctgtcca ctggtgagga gttcggcctg 
               
               
                   
               
               
                 541 
                 gtcgaggaga aggtgctctg ccgcatccac tacgacacca tgattgagaa cctcaagagg 
               
               
                   
               
               
                 601 
                 gccgccgaga acgggaacgg cctcacgttg gagggggcag tgccctcgga acaggacagt 
               
               
                   
               
               
                 661 
                 caacccaagc cggccaagcg cgcgcggacg tccttcaccg cggaacagct gcaggttatg 
               
               
                   
               
               
                 721 
                 caggcgcagt tcgcgcagga caacaacccc gacgctcaga cgctgcagaa gctggcggac 
               
               
                   
               
               
                 781 
                 atgacgggcc tcagccggag agtcatccag gtgtggtttc aaaactgccg ggcgcgtcat 
               
               
                   
               
               
                 841 
                 aaaaagcaca cgccgcaaca cccagtgccg ccctcggggg cgcccccgtc ccgccttccc 
               
               
                   
               
               
                 901 
                 tccgccctgt ccgacgacat ccactacacc ccgttcagca gccccgagcg ggcgcgcatg 
               
               
                   
               
               
                 961 
                 gtcaccctgc acggctacat tgagagtcat cctttttcag tactaacgct gccggcactt 
               
               
                   
               
               
                 1021 
                 ccgcatctgc ccgtgggcgc cccacagctg cccctcagcc gctgagatcc agtgtccaag 
               
               
                   
               
               
                 1081 
                 ctgcggccag gagtccaccc acctccgcat ccacccccgt ccgccatcct gcccaccacc 
               
               
                   
               
               
                 1141 
                 aggtcggttc ccgaggcctg gcctttccct ctcctgctga gaaccagaac ccaccaggag 
               
               
                   
               
               
                 1201 
                 caccacagag tcctcctctt ggaaggcaga actccctgaa atctggaatc agggtggaaa 
               
               
                   
               
               
                 1261 
                 cagcctgttt ttcccattta aacaggagtc ctcttcaact tcagctgatt acaataacaa 
               
               
                   
               
               
                 1321 
                 aaggcggaat tgaattgtgc gatgccaacg gccttctcat ttacaggttt ttttccccca 
               
               
                   
               
               
                 1381 
                 cattggcctt tatttactac ttccttggaa ccatctctga attctgaata gctgacaacc 
               
               
                   
               
               
                 1441 
                 cccaatgtta tccactctgt tgcttttgtc tggaaaactc tacagtgttt gtgggatgtc 
               
               
                   
               
               
                 1501 
                 cccaaaggta agctatgttc taattttatc atttccatct gtctggttat gtcaagttaa 
               
               
                   
               
               
                 1561 
                 ttcagaaaga gaagagacag tgaccaaccc tgagaggcct aatagggcag agatggaggc 
               
               
                   
               
               
                 1621 
                 ctgcccagac taggaggcag cggggataga cagggaatgg ggagaagaaa gacccccatt 
               
               
                   
               
               
                 1681 
                 ggtttggaaa tcaaggagag ggcggtgaca tattggacca gaagaggcac tagccatttt 
               
               
                   
               
               
                 1741 
                 aaggagagga aagagaaaac tctggggtca gggagagacc ctacccccac ctaattatcc 
               
               
                   
               
               
                 1801 
                 agcatatatg taagaaacat agcagcgatg gtattcgatc tgtgccatga ctcttctgaa 
               
               
                   
               
               
                 1861 
                 tgtttggaca ggttagagtt ggggacccct gttggccact tgttgacctc tcatagtggt 
               
               
                   
               
               
                 1921 
                 gcttgggcca ggtcttctca atggaagggg aatcccttat aggggagagg gaacagagcc 
               
               
                   
               
               
                 1981 
                 cagtgaaatg gcagtcagaa tgttaaccct ggatccatct ctaagtagag agagggtgcc 
               
               
                   
               
               
                 2041 
                 cattgcctag gtgagtgtgc caagctcagg attccaactg gtgcctctga gcttcccaat 
               
               
                   
               
               
                 2101 
                 caatacttcc tggagccagc cccacccacc cctgagaaca gaggtcagac acagctgcgt 
               
               
                   
               
               
                 2161 
                 aacatccatc ctgctacaac tcttccaccc caaacaaaag ggctcaggct acacacgacc 
               
               
                   
               
               
                 2221 
                 atgatttatg ttttcagggg atgcccattt gtcccaagct tatcctgtaa ttctagaatt 
               
               
                   
               
               
                 2281 
                 acctggtgtc ctgatgcatt ttccactaga ggttgctaat cagcatgttt tagcccaagt 
               
               
                   
               
               
                 2341 
                 ccaccttcct gctgtggtta acctgttatg ttgcttttgg aaggagactc taagacaggg 
               
               
                   
               
               
                 2401 
                 aaagcaagtt catggtacat acgcagccat tgtctctgtt tttacccatg gcagacattg 
               
               
                   
               
               
                 2461 
                 ctaatcaatg gcagctctat ttcactgagt ctggataagg tttcagagtt caaatgcttg 
               
               
                   
               
               
                 2521 
                 acgttggcac ttaacatgaa agcctatagg tcattcttgc tctgggatct acaggcaggg 
               
               
                   
               
               
                 2581 
                 taggcacagg tgcagcctaa gaagggaacc tgcttcctct cccttccaaa gacagtgaca 
               
               
                   
               
               
                 2641 
                 gctgactgag ggcaaagagc aggcaccact cagaacgtgg tgagtacagc tcagctcagc 
               
               
                   
               
               
                 2701 
                 actcagtcag tggtaacttg tgcccagccc tgtgctaggc gctgacatta acaggagcaa 
               
               
                   
               
               
                 2761 
                 ccagggccca attcctggcc ttggagctca aatctttcct ttgatttttg ctcctgatca 
               
               
                   
               
               
                 2821 
                 tcaaggcccc agtgg 
               
            
           
         
       
     
     By “LHX8 polypeptide” (or LIM homeobox 8) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. AAH40321.1. 
     
       
         
           
               
            
               
                 (SEQ ID NO: 55) 
               
               
                 MQILSRCQGLMSEECGRTTALAAGRTRKGAGEEGLVSPEGAGDEDSCSSS 
               
               
                   
               
               
                 APLSPSSSPRSMASGSGCPPGKCVCNSCGLEIVDKYLLKVNDLCWHVRCL 
               
               
                   
               
               
                 SCSVCRTSLGRHTSCYIKDKDIFCKLDYFRRYGTRCSRCGRHIHSTDWVR 
               
               
                   
               
               
                 RAKGNVYHLACFACFSCKRQLSTGEEFALVEEKVLCRVHYDCMLDNLKRE 
               
               
                   
               
               
                 VENGNGISVEGALLTEQDVNHPKPAKRARTSFTADQLQVMQAQFAQDNNP 
               
               
                   
               
               
                 DAQTLQKLAERTGLSRRVIQVWFQNCRARHKKHVSPNHSSSTPVTAAPPS 
               
               
                   
               
               
                 RLSPPMLEEMAYSAYVPQDGTMLTALHSYMDAHSPTTLGLQPLLPHSMTQ 
               
               
                   
               
               
                 LPISHT 
               
            
           
         
       
     
     By “LHX8 polynucleotide” (or LIM homeobox 8) is meant a polynucleotide encoding an LHX8 polypeptide. An exemplary LHX8 nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. BC040321. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 56) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 agcggcaaga ggctagcggc tggaccactt gtgctggagt ggtaaagaac tatcatgaat 
                   
               
               
                   
               
               
                 61 
                 ccatttactg aaagtgtcca tttctgaact caccctaaag aggacaaaca ccgcaaagta 
               
               
                   
               
               
                 121 
                 gttaaaagtc aggcattcgc gtcggacgtc tgggtttgaa ttctgccctg gcttgactgg 
               
               
                   
               
               
                 181 
                 aaacgcttcc cctatttctt ccgtagcgga ccgggagagc ttactggcgc tctgcgaacc 
               
               
                   
               
               
                 241 
                 ggctggaaag aaacaccgag tcactcgtac agactcttgg tcgcagaact tggctttccg 
               
               
                   
               
               
                 301 
                 ctattggtcc tccagaaccg cttgaaacaa ctggccccag ctggcgcatc agaccgcagt 
               
               
                   
               
               
                 361 
                 gaggaatgcc gcggggcggg tggcgaaggc agggtctgcc cgccagtgga ttcccgggtg 
               
               
                   
               
               
                 421 
                 tcccgcgtgg agcaggcttg cccagctggg aagcccatca aacctcagtc ttggcccaca 
               
               
                   
               
               
                 481 
                 gtgggagaga gaccagtggg tcccagacgg aggccatcgc ccgcttttgg cgacctccac 
               
               
                   
               
               
                 541 
                 tggcgtgaat aaaagcaccc ctctcttacc ctcagaaact gtgggtagca aggtataaaa 
               
               
                   
               
               
                 601 
                 cggagtctgg gaccggtaag tcccaaggtg agcccgtata cagctctgcc atctctgagg 
               
               
                   
               
               
                 661 
                 ggttatgcag attctgagca ggtgtcaggg gctcatgtca gaggagtgcg ggcggactac 
               
               
                   
               
               
                 721 
                 agccctggcg gccgggagga ctcgcaaagg cgccggggaa gagggactgg tgagccccga 
               
               
                   
               
               
                 781 
                 gggagcgggg gacgaggact cgtgctcctc ctcggccccg ctgtccccgt cgtcctcgcc 
               
               
                   
               
               
                 841 
                 ccggtccatg gcctcgggct ccggctgccc tcctggcaag tgtgtgtgca acagttgcgg 
               
               
                   
               
               
                 901 
                 cctggagatc gtggacaaat accttctcaa ggtgaatgac ctatgctggc atgtccggtg 
               
               
                   
               
               
                 961 
                 tctctcctgc agtgtttgca gaacctccct aggaaggcac accagctgtt atattaaaga 
               
               
                   
               
               
                 1021 
                 caaagacatt ttctgcaaac ttgattattt cagaaggtat ggaactcgct gctctcgatg 
               
               
                   
               
               
                 1081 
                 tgggagacac atccattcta ctgactgggt ccggagagcc aaggggaatg tctatcactt 
               
               
                   
               
               
                 1141 
                 ggcatgcttt gcctgctttt cctgcaaaag gcaactttcc acaggagagg agtttgcttt 
               
               
                   
               
               
                 1201 
                 ggtggaagag aaagtcctct gcagagtaca ttatgactgc atgctggata atttaaaaag 
               
               
                   
               
               
                 1261 
                 agaagtagaa aatgggaatg ggattagtgt ggaaggtgcc ctcctcacag agcaagatgt 
               
               
                   
               
               
                 1321 
                 taaccatcca aaaccagcaa aaagagctcg gaccagcttt acagcagatc agcttcaggt 
               
               
                   
               
               
                 1381 
                 tatgcaagca caatttgctc aggacaacaa cccagatgca cagacactcc agaaattggc 
               
               
                   
               
               
                 1441 
                 agaaaggaca ggcttgagca gacgtgtgat acaggtgtgg tttcagaatt gtagagcacg 
               
               
                   
               
               
                 1501 
                 ccacaagaaa cacgtcagtc ctaatcactc atcctccacc ccagtcacag cagccccacc 
               
               
                   
               
               
                 1561 
                 ctccaggctg tctccaccca tgttagaaga aatggcttat tctgcctacg tgccccaaga 
               
               
                   
               
               
                 1621 
                 tggaacgatg ttaactgcgc tgcatagtta tatggatgct cattcaccaa caactcttgg 
               
               
                   
               
               
                 1681 
                 actccagccc ttgttacccc attcaatgac acaactgcca ataagtcata cctaattctt 
               
               
                   
               
               
                 1741 
                 ttttcaggga tagacttgat taaggatata aatttgtcat ttattatgta taaaatacca 
               
               
                   
               
               
                 1801 
                 ttgaaaagat attactgtta attttttatt taacacctaa agcatttcca acatcacttt 
               
               
                   
               
               
                 1861 
                 gctgcccagg tatgtatcta tagttggcct gcaagacact tttattaatt cttcattttt 
               
               
                   
               
               
                 1921 
                 tgtaaaactt atgtttacaa gaagaaaaca aatcaaaaca ttttttgtat tgtctggaaa 
               
               
                   
               
               
                 1981 
                 tagttcactc tagtgtgtat ctgttaattt atttgtcatc aaaagagcac tttgcctaaa 
               
               
                   
               
               
                 2041 
                 agaaaggact gacaagtgtg caaaatgttt acaatctttt gtgaaattgt agtttatcat 
               
               
                   
               
               
                 2101 
                 tagtttgtat ctgtaagtta ttgtaataaa tattacctgt attttttgtt atatacaact 
               
               
                   
               
               
                 2161 
                 ttatactttg aagcttgtat ctgtgaattt gcaactgaaa tttattttgc caatgttttc 
               
               
                   
               
               
                 2221 
                 tgaatgaact gaataaagct tctgttgtag catgccatgc aaacacatta ttgtgtttgt 
               
               
                   
               
               
                 2281 
                 ggttgatgaa ttatggctgt aaataacact atagtttaat aagcccacca ttctgagttt 
               
               
                   
               
               
                 2341 
                 attaaacatt ttccattctt gtgaaaattt caaaaaaaaa aaaaaaaaaa aaagaaaaaa 
               
               
                   
               
               
                 2401 
                 aaaaaaaaaa a 
               
            
           
         
       
     
     By “TBR1 polypeptide” (or T-box, brain 1 (TBR1)) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. NP_006584.1. 
     
       
         
           
               
            
               
                 (SEQ ID NO: 57) 
               
               
                 MQLEHCLSPSIMLSKKFLNVSSSYPHSGGSELVLHDHPIISTTDNLERSS 
               
               
                   
               
               
                 PLKKITRGMTNQSDTDNFPDSKDSPGDVQRSKLSPVLDGVSELRHSFDGS 
               
               
                   
               
               
                 AADRYLLSQSSQPQSAATAPSAMFPYPGQHGPAHPAFSIGSPSRYMAHHP 
               
               
                   
               
               
                 VITNGAYNSLLSNSSPQGYPTAGYPYPQQYGHSYQGAPFYQFSSTQPGLV 
               
               
                   
               
               
                 PGKAQVYLCNRPLWLKFHRHQTEMIITKQGRRMFPFLSFNISGLDPTAHY 
               
               
                   
               
               
                 NIFVDVILADPNHWRFQGGKWVPCGKADTNVQGNRVYMHPDSPNTGAHWM 
               
               
                   
               
               
                 RQEISFGKLKLTNNKGASNNNGQMVVLQSLHKYQPRLHVVEVNEDGTEDT 
               
               
                   
               
               
                 SQPGRVQTFTFPETQFIAVTAYQNTDITQLKIDHNPFAKGFRDNYDTIYT 
               
               
                   
               
               
                 GCDMDRLTPSPNDSPRSQIVPGARYAMAGSFLQDQFVSNYAKARFHPGAG 
               
               
                   
               
               
                 AGPGPGTDRSVPHTNGLLSPQQAEDPGAPSPQRWFVTPANNRLDFAASAY 
               
               
                   
               
               
                 DTATDFAGNAATLLSYAAAGVKALPLQAAGCTGRPLGYYADPSGWGARSP 
               
               
                   
               
               
                 PQYCGTKSGSVLPCWPNSAAAAARMAGANPYLGEEAEGLAAERSPLPPGA 
               
               
                   
               
               
                 AEDAKPKDLSDSSWIETPSSIKSIDSSDSGIYEQAKRRRISPADTPVSES 
               
               
                   
               
               
                 SSPLKSEVLAQRDCEKNCAKDISGYYGFYSHS 
               
            
           
         
       
     
     By “TBR1 polynucleotide” (or T-box, brain 1 (TBR1)) is meant a polynucleotide encoding an TBR1 polypeptide. An exemplary TBR1 nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. NM_006593. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 58) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 gtcgctacca ggagccaggt gattatccta attaatgtct atctaattaa attactgtca 
                   
               
               
                   
               
               
                 61 
                 gcagctaacc aatggcagga gccgtttcat cggctgcaca agcagcaaga tcaaaagtga 
               
               
                   
               
               
                 121 
                 gccttttctg attgctgcat agtgtcaatt ggccaatctc ttctcccagg gaaaaaaaaa 
               
               
                   
               
               
                 181 
                 agtaaatcaa acctttgaga agcatttgct ggttgaagtg ctttctgtct agtgaggggg 
               
               
                   
               
               
                 241 
                 tctgtggatt tctagtttat gataaatagg actttaaaaa ccagggacgg gagggcgagt 
               
               
                   
               
               
                 301 
                 gttcaggttc tagagctatg cagctggagc actgcctttc tccttctatc atgctctcca 
               
               
                   
               
               
                 361 
                 agaaatttct caatgtgagc agcagctacc cacattcagg cggatccgag cttgtcttgc 
               
               
                   
               
               
                 421 
                 acgatcatcc cattatctcg accactgaca acctggagag aagttcacct ttgaaaaaaa 
               
               
                   
               
               
                 481 
                 ttaccagggg gatgacgaat cagtcagata cagacaattt tcctgactcc aaggactcac 
               
               
                   
               
               
                 541 
                 caggggacgt ccagagaagt aaactctctc ctgtcttgga cggggtctct gagcttcgtc 
               
               
                   
               
               
                 601 
                 acagtttcga tggctctgct gcagatcgct acctcctctc tcagtccagc cagccacagt 
               
               
                   
               
               
                 661 
                 ctgcggccac tgctcccagt gccatgttcc cgtaccccgg ccagcacgga ccggcgcacc 
               
               
                   
               
               
                 721 
                 ccgccttctc catcggcagc cctagccgct acatggccca ccacccggtc atcaccaacg 
               
               
                   
               
               
                 781 
                 gagcctacaa cagcctcctg tccaactcct cgccgcaggg ataccccacg gccggctacc 
               
               
                   
               
               
                 841 
                 cctacccaca gcagtacggc cactcctacc aaggagctcc gttctaccag ttctcctcca 
               
               
                   
               
               
                 901 
                 cccagccggg gctggtgccc ggcaaagcac aggtgtacct gtgcaacagg cccctttggc 
               
               
                   
               
               
                 961 
                 tgaaatttca ccggcaccaa acggagatga tcatcaccaa acagggaagg cgcatgtttc 
               
               
                   
               
               
                 1021 
                 cttttttaag ttttaacatt tctggtctcg atcccacggc tcattacaat atttttgtgg 
               
               
                   
               
               
                 1081 
                 atgtgatttt ggcggatccc aatcactgga ggtttcaagg aggcaaatgg gttccttgcg 
               
               
                   
               
               
                 1141 
                 gcaaagcgga caccaatgtg caaggaaatc gggtctatat gcatccggat tcccccaaca 
               
               
                   
               
               
                 1201 
                 ctggggctca ctggatgcgc caagaaatct cttttggaaa attaaaactt acgaacaaca 
               
               
                   
               
               
                 1261 
                 aaggagcttc aaataacaat gggcagatgg tggttttaca gtccttgcac aagtaccagc 
               
               
                   
               
               
                 1321 
                 cccgcctgca tgtggtggaa gtgaacgagg acggcacgga ggacactagc cagcccggcc 
               
               
                   
               
               
                 1381 
                 gcgtgcagac gttcactttc cctgagactc agttcatcgc cgtcaccgcc taccagaaca 
               
               
                   
               
               
                 1441 
                 cggatattac acaactgaaa atagatcaca acccttttgc aaaaggattt cgggataatt 
               
               
                   
               
               
                 1501 
                 atgacacgat ctacaccggc tgtgacatgg accgcctgac cccctcgccc aacgactcgc 
               
               
                   
               
               
                 1561 
                 cgcgctcgca gatcgtgccc ggggcccgct acgccatggc cggctctttc ctgcaggacc 
               
               
                   
               
               
                 1621 
                 agttcgtgag caactacgcc aaggcccgct tccacccggg cgcgggcgcg ggccccgggc 
               
               
                   
               
               
                 1681 
                 cgggtacgga ccgcagcgtg ccgcacacca acgggctgct gtcgccgcag caggccgagg 
               
               
                   
               
               
                 1741 
                 acccgggcgc gccctcgccg caacgctggt ttgtgacgcc ggccaacaac cggctggact 
               
               
                   
               
               
                 1801 
                 tcgcggcctc ggcctatgac acggccacgg acttcgcggg caacgcggcc acgctgctct 
               
               
                   
               
               
                 1861 
                 cttacgcggc ggcgggcgtg aaggcgctgc cgctgcaggc tgcaggctgc actggccgcc 
               
               
                   
               
               
                 1921 
                 cgctcggcta ctacgccgac ccgtcgggct ggggcgcccg cagtcccccg cagtactgcg 
               
               
                   
               
               
                 1981 
                 gcaccaagtc gggctcggtg ctgccctgct ggcccaacag cgccgcggcc gccgcgcgca 
               
               
                   
               
               
                 2041 
                 tggccggcgc caatccctac ctgggcgagg aggccgaggg cctggccgcc gagcgctcgc 
               
               
                   
               
               
                 2101 
                 cgctgccgcc cggcgccgcc gaggacgcca agcccaagga cctgtccgat tccagctgga 
               
               
                   
               
               
                 2161 
                 tcgagacgcc ctcctcgatc aagtccatcg actccagcga ctcggggatt tacgagcagg 
               
               
                   
               
               
                 2221 
                 ccaagcggag gcggatctcg ccggccgaca cgcccgtgtc cgagagttcg tccccgctca 
               
               
                   
               
               
                 2281 
                 agagcgaggt gctggcccag cgggactgcg agaagaactg cgccaaggac attagcggct 
               
               
                   
               
               
                 2341 
                 actatggctt ctactcgcac agctaggccg cccctgcccg cccggccccg ccgcggcccg 
               
               
                   
               
               
                 2401 
                 gacccccagc cagcccctca cagctcttcc ccagctccgc ctccccacac tcctccttgc 
               
               
                   
               
               
                 2461 
                 gcacccactc attttatttg accctcgatg gccgtctgca gcgaataagt gcaggtctcc 
               
               
                   
               
               
                 2521 
                 gagcgtgatt ttaacctttt ttgcacagca gtctctgcaa ttagctcacc gaccttcaac 
               
               
                   
               
               
                 2581 
                 tttgctgtaa accttttggt tttcctactt actcttcttc tgtggagtta tcctcctaca 
               
               
                   
               
               
                 2641 
                 attcccctcc ccctcgtctt tctcttacct cctacttctc tttcttgtaa tgaaactctt 
               
               
                   
               
               
                 2701 
                 cacctttagg agacctgggc agtcctgtca ggcagcagcg attccgaccc gccaagtctc 
               
               
                   
               
               
                 2761 
                 ggcctccaca ttaaccatag gatgttgact ctagaacctg gacccaccca gcgcgtcctt 
               
               
                   
               
               
                 2821 
                 tcttatcccc gagtggatgg atggatggat ggatggtagg gatgttaata attttagtgg 
               
               
                   
               
               
                 2881 
                 aacaaagcct gtgaaatgat tgtacatagt gttaatttat tgtaacgaat ggctagtttt 
               
               
                   
               
               
                 2941 
                 tattctcgtc aaggcacaaa accagttcat gcttaacctt tttttccttt cctttctttg 
               
               
                   
               
               
                 3001 
                 cttttctttc tctcctctca tactttctct tctctctctt ttaattttct tgtgagataa 
               
               
                   
               
               
                 3061 
                 tattctaaga ggctctagaa acatgaaata ctcagtagtg atgggtttcc cacttctcct 
               
               
                   
               
               
                 3121 
                 caatccgttg catgaaataa ttactatgtg ccctaatgca cacaaatagc taaggagaat 
               
               
                   
               
               
                 3181 
                 ccacccaaac acctttaaag gataggtgtc tgttcatagg caagtcgatt aagtggcatg 
               
               
                   
               
               
                 3241 
                 atgcctgcaa agcaaagtca actggagttg tatgttcccc ccaccttcta aatagaatag 
               
               
                   
               
               
                 3301 
                 ctcgacatca gcaatattat tttgccttat ttgtttttcc ccaaagtgcc aaatccatta 
               
               
                   
               
               
                 3361 
                 ctggtctgtg caggtgccaa atatgctgac aaactgtttc tgaatatctt tcagtacccc 
               
               
                   
               
               
                 3421 
                 ttcaccttta tatgctgtaa atctttgtaa tgaatactct attaatgata tagatgactg 
               
               
                   
               
               
                 3481 
                 aattgttggt aactatagtg tagtctagtg aagatgaatt gtgtgagttg tatattttac 
               
               
                   
               
               
                 3541 
                 tgcattttag ttttgaaaat gacttcccca ccacctagaa acagctgaaa tttgacttcc 
               
               
                   
               
               
                 3601 
                 ttgggagaac actagcatta atgcaagtaa gactgatttt cccctaagtc ttgttatatt 
               
               
                   
               
               
                 3661 
                 tgataaggag cattaatccc cctggaaata gattagtagg atttctaatg ttgtgtagca 
               
               
                   
               
               
                 3721 
                 aacctatact tttttgtatt taaaaattaa tgtgaaatat gcatcataca caatattcaa 
               
               
                   
               
               
                 3781 
                 tctagattcc agtccatggg gggatttttc ctaataggaa ttcagggtct aaacgtgtgt 
               
               
                   
               
               
                 3841 
                 atattttggc tcttctgtaa atctaatgtt gtgattttta tatttgtttc gttttgtctg 
               
               
                   
               
               
                 3901 
                 tgaactgaat aatttataca agaacacact ccattgagaa acgttttgtt ttttgctcgt 
               
               
                   
               
               
                 3961 
                 ttgtatcgtc tgtgtataac aagtaaaata aacctggtaa aaacgc 
               
            
           
         
       
     
     By “SLC1A3 polypeptide” (or solute carrier family 1; glial high affinity glutamate transporter member 3 (SLC1A3)) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. BAG35230.1. 
     
       
         
           
               
            
               
                 (SEQ ID NO: 59) 
               
               
                 MTKSNGEEPKMGGRMERFQQGVRKRTLLAKKKVQNITKEDVKSYLFRNAF 
               
               
                   
               
               
                 VLLTVTAVIVGTILGFTLRPYRMSYREVKYFSFPGELLMRMLQMLVLPLI 
               
               
                   
               
               
                 ISSLVTGMAALDSKASGKMGMRAVVYYMTTTIIAVVIGIIIVIIIHPGKG 
               
               
                   
               
               
                 TKENMHREGKIVRVTAADAFLDLIRNMFPPNLVEACFKQFKTNYEKRSFK 
               
               
                   
               
               
                 VPIQANETLVGAVINNVSEAMETLTRITEELVPVPGSVNGVNALGLVVFS 
               
               
                   
               
               
                 MCFGFVIGNMKEQGQALREFFDSLNEAIMRLVAVIMWYAPVGILFLIAGK 
               
               
                   
               
               
                 IVEMEDMGVIGGQLAMYTVTVIVGLLIHAVIVLPLLYFLVTRKNPWVFIG 
               
               
                   
               
               
                 GLLQALITALGTSSSSATLPITFKCLEENNGVDKRVTRFVLPVGATINMD 
               
               
                   
               
               
                 GTALYEALAAIFIAQVNNFELNFGQIITISITATAASIGAAGIPQAGLVT 
               
               
                   
               
               
                 MVIVLTSVGLPTDDITLIIAVDWFLDRLRTTTNVLGDSLGAGIVEHLSRH 
               
               
                   
               
               
                 ELKNRDVEMGNSVIEENEMKKPYQLIAQDNETEKPIDSETKM 
               
            
           
         
       
     
     By “SLC1A3 polynucleotide” (or solute carrier family 1; glial high affinity glutamate transporter member 3 (SLC1A3)) is meant a polynucleotide encoding an SLC1A3 polypeptide. An exemplary SLC1A3 nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. AK312304. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 60) 
                   
               
            
           
           
               
               
               
            
               
                 1 
                 gatagtaact tgcagtttca gagcacatgc acactgtcag ggctagcctg cctgcttacg 
                   
               
               
                   
               
               
                 61 
                 cgcgctgcgg attgttgctc cgttgtacct gctggggaat tcacctcgtt actgcttgat 
               
               
                   
               
               
                 121 
                 atcttccacc ccttacaaaa tcagaaaagt tgtgttttct aataccaaag aggaggtttg 
               
               
                   
               
               
                 181 
                 gctttctgtg ggtgattccc agacactgaa gtgcaaagaa gagaccctcc tagaaaagta 
               
               
                   
               
               
                 241 
                 aaatatgact aaaagcaatg gagaagagcc caagatgggg ggcaggatgg agagattcca 
               
               
                   
               
               
                 301 
                 gcagggagtc cgtaaacgca cacttttggc caagaagaaa gtgcagaaca ttacaaagga 
               
               
                   
               
               
                 361 
                 ggatgttaaa agttacctgt ttcggaatgc ttttgtgctg ctcacagtca ccgctgtcat 
               
               
                   
               
               
                 421 
                 tgtgggtaca atccttggat ttaccctccg accatacaga atgagctacc gggaagtcaa 
               
               
                   
               
               
                 481 
                 gtacttctcc tttcctgggg aacttctgat gaggatgtta cagatgctgg tcttaccact 
               
               
                   
               
               
                 541 
                 tatcatctcc agtcttgtca caggaatggc ggcgctagat agtaaggcat cagggaagat 
               
               
                   
               
               
                 601 
                 gggaatgcga gctgtagtct attatatgac taccaccatc attgctgtgg tgattggcat 
               
               
                   
               
               
                 661 
                 aatcattgtc atcatcatcc atcctgggaa gggcacaaag gaaaacatgc acagagaagg 
               
               
                   
               
               
                 721 
                 caaaattgta cgagtgacag ctgcagatgc cttcctggac ttgatcagga acatgttccc 
               
               
                   
               
               
                 781 
                 tccaaatctg gtagaagcct gctttaaaca gtttaaaacc aactatgaga agagaagctt 
               
               
                   
               
               
                 841 
                 taaagtgccc atccaggcca acgaaacgct tgtgggtgct gtgataaaca atgtgtctga 
               
               
                   
               
               
                 901 
                 ggccatggag actcttaccc gaatcacaga ggagctggtc ccagttccag gatctgtgaa 
               
               
                   
               
               
                 961 
                 tggagtcaat gccctgggtc tagttgtctt ctccatgtgc ttcggttttg tgattggaaa 
               
               
                   
               
               
                 1021 
                 catgaaggaa caggggcagg ccctgagaga gttctttgat tctcttaacg aagccatcat 
               
               
                   
               
               
                 1081 
                 gagactggta gcagtaataa tgtggtatgc ccccgtgggt attctcttcc tgattgctgg 
               
               
                   
               
               
                 1141 
                 gaagattgtg gagatggaag acatgggtgt gattgggggg cagcttgcca tgtacaccgt 
               
               
                   
               
               
                 1201 
                 gactgtcatt gttggcttac tcattcacgc agtcatcgtc ttgccactcc tctacttctt 
               
               
                   
               
               
                 1261 
                 ggtaacacgg aaaaaccctt gggtttttat tggagggttg ctgcaagcac tcatcaccgc 
               
               
                   
               
               
                 1321 
                 tctggggacc tcttcaagtt ctgccaccct acccatcacc ttcaagtgcc tggaagagaa 
               
               
                   
               
               
                 1381 
                 caatggcgtg gacaagcgcg tcaccagatt cgtgctcccc gtaggagcca ccattaacat 
               
               
                   
               
               
                 1441 
                 ggatgggact gccctctatg aggctttggc tgccattttc attgctcaag ttaacaactt 
               
               
                   
               
               
                 1501 
                 tgaactgaac ttcggacaaa ttattacaat cagcatcaca gccacagctg ccagtattgg 
               
               
                   
               
               
                 1561 
                 ggcagctgga attcctcagg cgggcctggt cactatggtc attgtgctga catctgtcgg 
               
               
                   
               
               
                 1621 
                 cctgcccact gacgacatca cgctcatcat cgcggtggac tggttcctgg atcgcctccg 
               
               
                   
               
               
                 1681 
                 gaccaccacc aacgtactgg gagactccct gggagctggg attgtggagc acttgtcacg 
               
               
                   
               
               
                 1741 
                 acatgaactg aagaacagag atgttgaaat gggtaactca gtgattgaag agaatgaaat 
               
               
                   
               
               
                 1801 
                 gaagaaacca tatcaactga ttgcacagga caatgaaact gagaaaccca tcgacagtga 
               
               
                   
               
               
                 1861 
                 aaccaagatg tag 
               
            
           
         
       
     
     By “TH polypeptide” (or tyrosine hydroxylase) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. AAI43612.1. 
     
       
         
           
               
            
               
                 (SEQ ID NO: 61) 
               
               
                 MPTPDATTPQAKGFRRAVSELDAKQAEAIMSPRFIGRRQSLIEDARKERE 
               
               
                   
               
               
                 AAVAAAAAAVPSEPGDPLEAVAFEEKEGKAVLNLLFSPRATKPSALSRAV 
               
               
                   
               
               
                 KVFETFEAKIHHLETRPAQRPRAGGPHLEYFVRLEVRRGDLAALLSGVRQ 
               
               
                   
               
               
                 VSEDVRSPAGPKVPWFPRKVSELDKCHHLVTKFDPDLDLDHPGFSDQVYR 
               
               
                   
               
               
                 QRRKLIAEIAFQYRHGDPIPRVEYTAEEIATWKEVYTTLKGLYATHACGE 
               
               
                   
               
               
                 HLEAFALLERFSGYREDNIPQLEDVSRFLKERTGFQLRPVAGLLSARDFL 
               
               
                   
               
               
                 ASLAFRVFQCTQYIRHASSPMHSPEPDCCHELLGHVPMLADRTFAQFSQD 
               
               
                   
               
               
                 IGLASLGASDEEIEKLSTLYWFTVEFGLCKQNGEVKAYGAGLLSSYGELL 
               
               
                   
               
               
                 HCLSEEPEIRAFDPEAAAVQPYQDQTYQSVYFVSESFSDAKDKLRSYASR 
               
               
                   
               
               
                 IQRPFSVKFDPYTLAIDVLDSPQAVRRSLEGVQDELDTLAHALSAIG 
               
            
           
         
       
     
     By “TH polynucleotide” (or tyrosine hydroxylase) is meant a polynucleotide encoding an TH polypeptide. An exemplary TH nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. BC143611. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 62) 
                   
               
            
           
           
               
               
               
            
               
                    1 
                 acccagaggg ggctttgacg tcagctcagc ttataagagg ctgctgggcc agggctgtgg 
                   
               
               
                   
               
               
                   61 
                 agacggagcc cggacctcca cactgagcca tgcccacccc cgacgccacc acgccacagg 
               
               
                   
               
               
                  121 
                 ccaagggctt ccgcagggcc gtgtctgagc tggacgccaa gcaggcagag gccatcatgt 
               
               
                   
               
               
                  181 
                 ccccgcggtt cattgggcgc aggcagagcc tcatcgagga cgcccgcaag gagcgggagg 
               
               
                   
               
               
                  241 
                 cggcggtggc agcagcggcc gctgcagtcc cctcggagcc cggggacccc ctggaggctg 
               
               
                   
               
               
                  301 
                 tggcctttga ggagaaggag gggaaggccg tgctaaacct gctcttctcc ccgagggcca 
               
               
                   
               
               
                  361 
                 ccaagccctc ggcgctgtcc cgagctgtga aggtgtttga gacgtttgaa gccaaaatcc 
               
               
                   
               
               
                  421 
                 accatctaga gacccggccc gcccagaggc cgcgagctgg gggcccccac ctggagtact 
               
               
                   
               
               
                  481 
                 tcgtgcgcct cgaggtgcgc cgaggggacc tggccgccct gctcagtggt gtgcgccagg 
               
               
                   
               
               
                  541 
                 tgtcagagga cgtgcgcagc cccgcggggc ccaaggtccc ctggttccca agaaaagtgt 
               
               
                   
               
               
                  601 
                 cagagctgga caagtgtcat cacctggtca ccaagttcga ccctgacctg gacttggacc 
               
               
                   
               
               
                  661 
                 acccgggctt ctcggaccag gtgtaccgcc agcgcaggaa gctgattgct gagatcgcct 
               
               
                   
               
               
                  721 
                 tccagtacag gcacggcgac ccgattcccc gtgtggagta caccgccgag gagattgcca 
               
               
                   
               
               
                  781 
                 cctggaagga ggtctacacc acgctgaagg gcctctacgc cacgcacgcc tgcggggagc 
               
               
                   
               
               
                  841 
                 acctggaggc ctttgctttg ctggagcgct tcagcggcta ccgggaagac aatatccccc 
               
               
                   
               
               
                  901 
                 agctggagga cgtctcccgc ttcctgaagg agcgcacggg cttccagctg cggcctgtgg 
               
               
                   
               
               
                  961 
                 ccggcctgct gtccgcccgg gacttcctgg ccagcctggc cttccgcgtg ttccagtgca 
               
               
                   
               
               
                 1021 
                 cccagtatat ccgccacgcg tcctcgccca tgcactcccc tgagccggac tgctgccacg 
               
               
                   
               
               
                 1081 
                 agctgctggg gcacgtgccc atgctggccg accgcacctt cgcgcagttc tcgcaggaca 
               
               
                   
               
               
                 1141 
                 ttggcctggc gtccctgggg gcctcggatg aggaaattga gaagctgtcc acgctgtact 
               
               
                   
               
               
                 1201 
                 ggttcacggt ggagttcggg ctgtgtaagc agaacgggga ggtgaaggcc tatggtgccg 
               
               
                   
               
               
                 1261 
                 ggctgctgtc ctcctacggg gagctcctgc actgcctgtc tgaggagcct gagattcggg 
               
               
                   
               
               
                 1321 
                 ccttcgaccc tgaggctgcg gccgtgcagc cctaccaaga ccagacgtac cagtcagtct 
               
               
                   
               
               
                 1381 
                 acttcgtgtc tgagagcttc agtgacgcca aggacaagct caggagctat gcctcacgca 
               
               
                   
               
               
                 1441 
                 tccagcgccc cttctccgtg aagttcgacc cgtacacgct ggccatcgac gtgctggaca 
               
               
                   
               
               
                 1501 
                 gcccccaggc cgtgcggcgc tccctggagg gtgtccagga tgagctggac acccttgccc 
               
               
                   
               
               
                 1561 
                 atgcgctgag tgccattggc taggtgcacg gcgtccctga gggcccttcc caacctcccc 
               
               
                   
               
               
                 1621 
                 tggtcctgc 
               
            
           
         
       
     
     By “Neurofilament 200 polypeptide” (or neurofilament heavy (NEFH)) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. NP_066554.2. 
     
       
         
           
               
            
               
                 (SEQ ID NO: 63) 
               
               
                 MMSFGGADALLGAPFAPLHGGGSLHYALARKGGAGGTRSAAGSSSGFHSW 
               
               
                   
               
               
                 TRTSVSSVSASPSRFRGAGAASSTDSLDTLSNGPEGCMVAVATSRSEKEQ 
               
               
                   
               
               
                 LQALNDRFAGYIDKVRQLEAHNRSLEGEAAALRQQQAGRSAMGELYEREV 
               
               
                   
               
               
                 REMRGAVLRLGAARGQLRLEQEHLLEDIAHVRQRLDDEARQREEAEAAAR 
               
               
                   
               
               
                 ALARFAQEAEAARVDLQKKAQALQEECGYLRRHHQEEVGELLGQIQGSGA 
               
               
                   
               
               
                 AQAQMQAETRDALKCDVTSALREIRAQLEGHAVQSTLQSEEWFRVRLDRL 
               
               
                   
               
               
                 SEAAKVNTDAMRSAQEEITEYRRQLQARTTELEALKSTKDSLERQRSELE 
               
               
                   
               
               
                 DRHQADIASYQEAIQQLDAELRNTKWEMAAQLREYQDLLNVKMALDIEIA 
               
               
                   
               
               
                 AYRKLLEGEECRIGFGPIPFSLPEGLPKIPSVSTHIKVKSEEKIKVVEKS 
               
               
                   
               
               
                 EKETVIVEEQTEETQVTEEVTEEEEKEAKEEEGKEEEGGEEEEAEGGEEE 
               
               
                   
               
               
                 TKSPPAEEAASPEKEAKSPVKEEAKSPAEAKSPEKEEAKSPAEVKSPEKA 
               
               
                   
               
               
                 KSPAKEEAKSPPEAKSPEKEEAKSPAEVKSPEKAKSPAKEEAKSPAEAKS 
               
               
                   
               
               
                 PEKAKSPVKEEAKSPAEAKSPVKEEAKSPAEVKSPEKAKSPTKEEAKSPE 
               
               
                   
               
               
                 KAKSPEKEEAKSPEKAKSPVKAEAKSPEKAKSPVKAEAKSPEKAKSPVKE 
               
               
                   
               
               
                 EAKSPEKAKSPVKEEAKSPEKAKSPVKEEAKTPEKAKSPVKEEAKSPEKA 
               
               
                   
               
               
                 KSPEKAKTLDVKSPEAKTPAKEEARSPADKFPEKAKSPVKEEVKSPEKAK 
               
               
                   
               
               
                 SPLKEDAKAPEKEIPKKEEVKSPVKEEEKPQEVKVKEPPKKAEEEKAPAT 
               
               
                   
               
               
                 PKTEEKKDSKKEEAPKKEAPKPKVEEKKEPAVEKPKESKVEAKKEEAEDK 
               
               
                   
               
               
                 KKVPTPEKEAPAKVEVKEDAKPKEKTEVAKKEPDDAKAKEPSKPAEKKEA 
               
               
                   
               
               
                 APEKKDTKEEKAKKPEEKPKTEAKAKEDDKTLSKEPSKPKAEKAEKSSST 
               
               
                   
               
               
                 DQKDSKPPEKATEDKAAKGK 
               
            
           
         
       
     
     By “Neurofilament 200 polynucleotide” (or neurofilament heavy (NEFH)) is meant a polynucleotide encoding an Neurofilament 200 polypeptide. An exemplary Neurofilament 200 nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. NM_021076. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 64) 
                   
               
            
           
           
               
               
               
            
               
                    1 
                 aaaagggccg gcgccctggt gctgccgcag tgcctcccgc cccgtcccgg cctcgcgcac 
                   
               
               
                   
               
               
                   61 
                 ctgctcaggc catgatgagc ttcggcggcg cggacgcgct gctgggcgcc ccgttcgcgc 
               
               
                   
               
               
                  121 
                 cgctgcatgg cggcggcagc ctccactacg cgctagcccg aaagggtggc gcaggcggga 
               
               
                   
               
               
                  181 
                 cgcgctccgc cgctggctcc tccagcggct tccactcgtg gacacggacg tccgtgagct 
               
               
                   
               
               
                  241 
                 ccgtgtccgc ctcgcccagc cgcttccgtg gcgcaggcgc cgcctcaagc accgactcgc 
               
               
                   
               
               
                  301 
                 tggacacgct gagcaacggg ccggagggct gcatggtggc ggtggccacc tcacgcagtg 
               
               
                   
               
               
                  361 
                 agaaggagca gctgcaggcg ctgaacgacc gcttcgccgg gtacatcgac aaggtgcggc 
               
               
                   
               
               
                  421 
                 agctggaggc gcacaaccgc agcctggagg gcgaggctgc ggcgctgcgg cagcagcagg 
               
               
                   
               
               
                  481 
                 cgggccgctc cgctatgggc gagctgtacg agcgcgaggt ccgcgagatg cgcggcgcgg 
               
               
                   
               
               
                  541 
                 tgctgcgcct gggcgcggcg cgcggtcagc tacgcctgga gcaggagcac ctgctcgagg 
               
               
                   
               
               
                  601 
                 acatcgcgca cgtgcgccag cgcctagacg acgaggcccg gcagcgagag gaggccgagg 
               
               
                   
               
               
                  661 
                 cggcggcccg cgcgctggcg cgcttcgcgc aggaggccga ggcggcgcgc gtggacctgc 
               
               
                   
               
               
                  721 
                 agaagaaggc gcaggcgctg caggaggagt gcggctacct gcggcgccac caccaggaag 
               
               
                   
               
               
                  781 
                 aggtgggcga gctgctcggc cagatccagg gctccggcgc cgcgcaggcg cagatgcagg 
               
               
                   
               
               
                  841 
                 ccgagacgcg cgacgccctg aagtgcgacg tgacgtcggc gctgcgcgag attcgcgcgc 
               
               
                   
               
               
                  901 
                 agcttgaagg ccacgcggtg cagagcacgc tgcagtccga ggagtggttc cgagtgaggc 
               
               
                   
               
               
                  961 
                 tggaccgact gtcggaggca gccaaggtga acacagacgc tatgcgctca gcgcaggagg 
               
               
                   
               
               
                 1021 
                 agataactga gtaccggcgt cagctgcagg ccaggaccac agagctggag gcactgaaaa 
               
               
                   
               
               
                 1081 
                 gcaccaagga ctcactggag aggcagcgct ctgagctgga ggaccgtcat caggccgaca 
               
               
                   
               
               
                 1141 
                 ttgcctccta ccaggaagcc attcagcagc tggacgctga gctgaggaac accaagtggg 
               
               
                   
               
               
                 1201 
                 agatggccgc ccagctgcga gaataccagg acctgctcaa tgtcaagatg gctctggata 
               
               
                   
               
               
                 1261 
                 tagagatagc cgcttacaga aaactcctgg aaggtgaaga gtgtcggatt ggctttggcc 
               
               
                   
               
               
                 1321 
                 caattccttt ctcgcttcca gaaggactcc ccaaaattcc ctctgtgtcc actcacataa 
               
               
                   
               
               
                 1381 
                 aggtgaaaag cgaagagaag atcaaagtgg tggagaagtc tgagaaagaa actgtgattg 
               
               
                   
               
               
                 1441 
                 tggaggaaca gacagaggag acccaagtga ctgaagaagt gactgaagaa gaggagaaag 
               
               
                   
               
               
                 1501 
                 aggccaaaga ggaggagggc aaggaggaag aagggggtga agaagaggag gcagaagggg 
               
               
                   
               
               
                 1561 
                 gagaagaaga aacaaagtct cccccagcag aagaggctgc atccccagag aaggaagcca 
               
               
                   
               
               
                 1621 
                 agtcaccagt aaaggaagag gcaaagtcac cggctgaggc caagtcccca gagaaggagg 
               
               
                   
               
               
                 1681 
                 aagcaaaatc cccagccgaa gtcaagtccc ctgagaaggc caagtctcca gcaaaggaag 
               
               
                   
               
               
                 1741 
                 aggcaaagtc accgcctgag gccaagtccc cagagaagga ggaagcaaaa tctccagctg 
               
               
                   
               
               
                 1801 
                 aggtcaagtc ccccgagaag gccaagtccc cagcaaagga agaggcaaag tcaccggctg 
               
               
                   
               
               
                 1861 
                 aggccaagtc tccagagaag gccaagtccc cagtgaagga agaagcaaag tcaccggctg 
               
               
                   
               
               
                 1921 
                 aggccaagtc cccagtgaag gaagaagcaa aatctccagc tgaggtcaag tccccggaaa 
               
               
                   
               
               
                 1981 
                 aggccaagtc tccaacgaag gaggaagcaa agtcccctga gaaggccaag tccccagaga 
               
               
                   
               
               
                 2041 
                 aggaagaggc caagtcccct gagaaggcca agtccccagt gaaggcagaa gcaaagtccc 
               
               
                   
               
               
                 2101 
                 ctgagaaggc caagtcccca gtgaaggcag aagcaaagtc ccctgagaag gccaagtccc 
               
               
                   
               
               
                 2161 
                 cagtgaagga agaagcaaag tcccctgaga aggccaagtc cccagtgaag gaagaagcaa 
               
               
                   
               
               
                 2221 
                 agtcccctga gaaggccaag tccccagtga aggaagaagc aaagaccccc gagaaggcca 
               
               
                   
               
               
                 2281 
                 agtccccagt gaaggaagaa gctaagtccc cagagaaggc caagtcccca gagaaggcca 
               
               
                   
               
               
                 2341 
                 agactcttga tgtgaagtct ccagaagcca agactccagc gaaggaggaa gcaaggtccc 
               
               
                   
               
               
                 2401 
                 ctgcagacaa attccctgaa aaggccaaaa gccctgtcaa ggaggaggtc aagtccccag 
               
               
                   
               
               
                 2461 
                 agaaggcgaa atctcccctg aaggaggatg ccaaggcccc tgagaaggag atcccaaaaa 
               
               
                   
               
               
                 2521 
                 aggaagaggt gaagtcccca gtgaaggagg aggagaagcc ccaggaggtg aaagtcaaag 
               
               
                   
               
               
                 2581 
                 agcccccaaa gaaggcagag gaagagaaag cccctgccac accaaaaaca gaggagaaga 
               
               
                   
               
               
                 2641 
                 aggacagcaa gaaagaggag gcacccaaga aggaggctcc aaagcccaag gtggaggaga 
               
               
                   
               
               
                 2701 
                 agaaggaacc tgctgtcgaa aagcccaaag aatccaaagt tgaagccaag aaggaagagg 
               
               
                   
               
               
                 2761 
                 ctgaagataa gaaaaaagtc cccaccccag agaaggaggc tcctgccaag gtggaggtga 
               
               
                   
               
               
                 2821 
                 aggaagacgc taaacccaaa gaaaagacag aggtagccaa gaaggaacca gatgatgcca 
               
               
                   
               
               
                 2881 
                 aggccaagga acccagcaaa ccagcagaga agaaggaggc agcaccggag aaaaaagaca 
               
               
                   
               
               
                 2941 
                 ccaaggagga gaaggccaag aagcctgagg agaaacccaa gacagaggcc aaagccaagg 
               
               
                   
               
               
                 3001 
                 aagatgacaa gaccctctca aaagagccta gcaagcctaa ggcagaaaag gctgaaaaat 
               
               
                   
               
               
                 3061 
                 cctccagcac agaccaaaaa gacagcaagc ctccagagaa ggccacagaa gacaaggccg 
               
               
                   
               
               
                 3121 
                 ccaaggggaa gtaaggcagg gagaaaggaa catccggaac agccaaagaa actcagaaga 
               
               
                   
               
               
                 3181 
                 gtcccggagc tcaaggatca gagtaacaca attttcactt tttctgtctt tatgtaagaa 
               
               
                   
               
               
                 3241 
                 gaaactgctt agatgacggg gcctccttct tcaaacagga atttctgtta gcaatatgtt 
               
               
                   
               
               
                 3301 
                 agcaagagag ggcactccca ggcccctgcc cccaggccct ccccaggcga tggacaatta 
               
               
                   
               
               
                 3361 
                 tgatagctta tgtagctgaa tgtgatacat gccgaatgcc acacgtaaac acttgactat 
               
               
                   
               
               
                 3421 
                 aaaaactgcc cccctccttt ccaaataagt gcatttattg cctctatgtg caactgacag 
               
               
                   
               
               
                 3481 
                 atgaccgcaa taatgaatga gcagttagaa atacattatg cttgagatgt cttaacctat 
               
               
                   
               
               
                 3541 
                 tcccaaatgc cttctgtttt ccaaaggagt ggtcaagccc ttgcccagag ctctctattc 
               
               
                   
               
               
                 3601 
                 tggaagagcg gtccaggtgg ggccggggac tggccactga attatgccag ggcgcacttt 
               
               
                   
               
               
                 3661 
                 ccactggagt tcactttcaa ttgcttctgt gcaataaaac caagtgctta taaaatgaaa 
               
               
                   
               
               
                 3721 
                 a 
               
            
           
         
       
     
     By “Map2” (or microtubule-associated protein 2) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. AAH38857.1. 
     
       
         
           
               
            
               
                 (SEQ ID NO: 65) 
               
               
                 MADERKDEAKAPHWTSAPLTEASAHSHPPEIKDQGGAGEGLVRSANGFPY 
               
               
                   
               
               
                 REDEEGAFGEHGSQGTYSNTKENGINGELTSADRETAEEVSARIVQVVTA 
               
               
                   
               
               
                 EAVAVLKGEQEKEAQHKDQTAALPLAAEETANLPPSPPPSPASEQTVTVE 
               
               
                   
               
               
                 EAAGGESALAPSVFKQAKDKVSNSTLSKIPALQGSTKSPRYSSACPSTTK 
               
               
                   
               
               
                 RATFSDSLLIQPTSAGSTDRLPYSKSGNKDGVTKSPEKRSSLPRPSSILP 
               
               
                   
               
               
                 PRRGVSGDRDENSFSLNSSISSSARRTTRSEPIRRAGKSGTSTPTTPGST 
               
               
                   
               
               
                 AITPGTPPSYSSRTPGTPGTPSYPRTPHTPGTPKSAILVPSEKKVAIIRT 
               
               
                   
               
               
                 PPKSPATPKQLRLINQPLPDLKNVKSKIGSTDNIKYQPKGGQVRILNKKI 
               
               
                   
               
               
                 DFSKVQSRCGSKDNIKHSAGGGNVQIVTKKIDLSHVTSKCGSLKNIRHRP 
               
               
                   
               
               
                 GGGRVKIESVKLDFKEKAQAKVGSLDNAHHVPGGGNVKIDSQKLNFREHA 
               
               
                   
               
               
                 KARVDHGAEIITQSPGRSSVASPRRLSNVSSSGSINLLESPQLATLAEDV 
               
               
                   
               
               
                 TAALAKQGL 
               
            
           
         
       
     
     By “Map2 polynucleotide” (or microtubule-associated protein 2) is meant a polynucleotide encoding an Map2 polypeptide. An exemplary Map2 nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. BC038857. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 66) 
                   
               
            
           
           
               
               
               
            
               
                    1 
                 ggcgctcggg ctgcgcgggc tctgggcagc agcagcagca gcagcagcat cctctcttcc 
                   
               
               
                   
               
               
                   61 
                 tttacttccc ttccgcttct ttctcttcct tctccttctt tttccccccc ctccccttct 
               
               
                   
               
               
                  121 
                 tcccctaacc cttctacccc tctccttttt ctccggaggg cgctaagtcc gtgagcggtg 
               
               
                   
               
               
                  181 
                 gcagtcgcga ccgcgggtgc atccagtttc tgcgcccaga ttttattgat ctaatccaaa 
               
               
                   
               
               
                  241 
                 gtatcttata acttctggct ggaattaaga ttcttcagct tgtctctaac cgaggaagca 
               
               
                   
               
               
                  301 
                 ttgattggga gctactcatt cagaaaatta aaagaaagaa gccagaaaat attatcaacc 
               
               
                   
               
               
                  361 
                 ctttgagaac acgacacaac gaactttata ttttaccact tccttgaata gttgcaggag 
               
               
                   
               
               
                  421 
                 aaataacaag gcattgaaga atggcagatg aacggaaaga cgaagcaaag gcacctcact 
               
               
                   
               
               
                  481 
                 ggacctcagc accgctaaca gaggcatctg cacactcaca tccacctgag attaaggatc 
               
               
                   
               
               
                  541 
                 aaggcggagc aggggaagga cttgtccgaa gcgccaatgg attcccatac agggaggatg 
               
               
                   
               
               
                  601 
                 aagagggtgc ctttggagag catgggtcac agggcaccta ttcaaatacc aaagagaatg 
               
               
                   
               
               
                  661 
                 ggatcaacgg agagctgacc tcagctgaca gagaaacagc agaggaggtg tctgcaagga 
               
               
                   
               
               
                  721 
                 tagttcaagt agtcactgct gaggctgtag cagtcctgaa aggtgaacaa gagaaagaag 
               
               
                   
               
               
                  781 
                 ctcaacataa agaccagact gcagctctgc ctttagcagc tgaagaaaca gctaatctgc 
               
               
                   
               
               
                  841 
                 ctccttctcc acccccatca cctgcctcag aacagactgt cacagtggag gaagcagcag 
               
               
                   
               
               
                  901 
                 gtggggaatc agctctggct cccagtgtat ttaaacaggc aaaggacaaa gtctctaatt 
               
               
                   
               
               
                  961 
                 ctaccttgtc aaagattcct gctttacagg gtagcacaaa gtccccaaga tacagctcag 
               
               
                   
               
               
                 1021 
                 cctgccctag cacgactaaa agggctacat tttctgacag tttattaata cagcccacct 
               
               
                   
               
               
                 1081 
                 cagcaggctc cacagaccgt ttgccatact caaaatcagg gaacaaggac ggagtaacca 
               
               
                   
               
               
                 1141 
                 agagcccaga aaagcgctct tctctcccaa gaccttcctc cattctccct cctcggcgag 
               
               
                   
               
               
                 1201 
                 gtgtgtcagg agacagagat gagaattcct tctctctcaa cagttctatc tcttcttcag 
               
               
                   
               
               
                 1261 
                 cacggcggac caccaggtca gagccaattc gcagagcagg gaagagtggt acctcaacac 
               
               
                   
               
               
                 1321 
                 ccactacccc tgggtctact gccatcactc ctggcacccc accaagttat tcttcacgca 
               
               
                   
               
               
                 1381 
                 caccaggcac tcctggaacc cctagctatc ccaggacccc tcacacacca ggaaccccca 
               
               
                   
               
               
                 1441 
                 agtctgccat cttggtgccg agtgagaaga aggtcgccat catacgtact cctccaaaat 
               
               
                   
               
               
                 1501 
                 ctcctgcgac tcccaagcag cttcggctta ttaaccaacc actgccagac ctgaagaatg 
               
               
                   
               
               
                 1561 
                 tcaaatccaa aatcggatca acagacaaca tcaaatacca gcctaaaggg gggcaggtta 
               
               
                   
               
               
                 1621 
                 ggattttaaa caagaagatc gattttagca aagttcagtc cagatgtggt tccaaggata 
               
               
                   
               
               
                 1681 
                 acatcaaaca ttcggctggg ggcggaaatg tacaaattgt taccaagaaa atagacctaa 
               
               
                   
               
               
                 1741 
                 gccatgtgac atccaaatgt ggctctctga agaacatccg ccacaggcca ggtggcggac 
               
               
                   
               
               
                 1801 
                 gtgtgaaaat tgagagtgta aaactagatt tcaaagaaaa ggcccaagct aaagttggtt 
               
               
                   
               
               
                 1861 
                 ctcttgataa tgctcatcat gtacctggag gtggtaatgt caagattgac agccaaaagt 
               
               
                   
               
               
                 1921 
                 tgaacttcag agagcatgct aaagcccgtg tggaccatgg ggctgagatc attacacagt 
               
               
                   
               
               
                 1981 
                 ccccaggcag atccagcgtg gcatcacccc gacgactcag caatgtctcc tcgtctggaa 
               
               
                   
               
               
                 2041 
                 gcatcaacct gctcgaatct cctcagcttg ccactttggc tgaggatgtc actgctgcac 
               
               
                   
               
               
                 2101 
                 tcgctaagca gggcttgtga atatttctca tttagcattg aaataataat atttaggcat 
               
               
                   
               
               
                 2161 
                 gagctcttgg caggagtggg ctctgagcag ttgttatatt cattctttat aaaccataaa 
               
               
                   
               
               
                 2221 
                 ataaataatc tcatccccaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 
               
               
                   
               
               
                 2281 
                 aaaaaa 
               
            
           
         
       
     
     By “DCX” (or doublecortin) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. NP_835366.1. 
     
       
         
           
               
            
               
                 (SEQ ID NO: 67) 
               
               
                 MELDFGHFDERDKTSRNMRGSRMNGLPSPTHSAHCSFYRTRTLQALSNEK 
               
               
                   
               
               
                 KAKKVRFYRNGDRYFKGIVYAVSSDRFRSFDALLADLTRSLSDNINLPQG 
               
               
                   
               
               
                 VRYIYTIDGSRKIGSMDELEEGESYVCSSDNFFKKVEYTKNVNPNWSVNV 
               
               
                   
               
               
                 KTSANMKAPQSLASSNSAQARENKDFVRPKLVTIIRSGVKPRKAVRVLLN 
               
               
                   
               
               
                 KKTAHSFEQVLTDITEAIKLETGVVKKLYTLDGKQVTCLHDFFGDDDVFI 
               
               
                   
               
               
                 ACGPEKFRYAQDDFSLDENECRVMKGNPSATAGPKASPTPQKTSAKSPGP 
               
               
                   
               
               
                 MRRSKSPADSANGTSSSQLSTPKSKQSPISTPTSPGSLRKHKDLYLPLSL 
               
               
                   
               
               
                 DDSDSLGDSM 
               
            
           
         
       
     
     By “DCX polynucleotide” (or doublecortin) is meant a polynucleotide encoding an DCX polypeptide. An exemplary DCX nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. NM_178153. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 68) 
                   
               
            
           
           
               
               
               
            
               
                    1 
                 ctggcaggaa tttcttgctt ggagctcaga caacaaaggc atagagagat tggttttctt 
                   
               
               
                   
               
               
                   61 
                 tctctcagca tctccaccca accagcagaa aaccggtctc tgaggttcca ccaaaatatg 
               
               
                   
               
               
                  121 
                 gaacttgatt ttggacactt tgacgaaaga gataagacat ccaggaacat gcgaggctcc 
               
               
                   
               
               
                  181 
                 cggatgaatg ggttgcctag ccccactcac agcgcccact gtagcttcta ccgaaccaga 
               
               
                   
               
               
                  241 
                 accttgcagg cactgagtaa tgagaagaaa gccaagaagg tacgtttcta ccgcaatggg 
               
               
                   
               
               
                  301 
                 gaccgctact tcaaggggat tgtgtacgct gtgtcctctg accgttttcg cagctttgac 
               
               
                   
               
               
                  361 
                 gccttgctgg ctgacctgac gcgatctctg tctgacaaca tcaacctgcc tcagggagtg 
               
               
                   
               
               
                  421 
                 cgttacattt acaccattga tggatccagg aagatcggaa gcatggatga actggaggaa 
               
               
                   
               
               
                  481 
                 ggggaaagct atgtctgttc ctcagacaac ttctttaaaa aggtggagta caccaagaat 
               
               
                   
               
               
                  541 
                 gtcaatccca actggtctgt caacgtaaaa acatctgcca atatgaaagc cccccagtcc 
               
               
                   
               
               
                  601 
                 ttggctagca gcaacagtgc acaggccagg gagaacaagg actttgtgcg ccccaagctg 
               
               
                   
               
               
                  661 
                 gttaccatca tccgcagtgg ggtgaagcct cggaaggctg tgcgtgtgct tctgaacaag 
               
               
                   
               
               
                  721 
                 aagacagccc actcttttga gcaagtcctc actgatatca cagaagccat caaactggag 
               
               
                   
               
               
                  781 
                 accggggttg tcaaaaaact ctacactctg gatggaaaac aggtaacttg tctccatgat 
               
               
                   
               
               
                  841 
                 ttctttggtg atgatgatgt gtttattgcc tgtggtcctg aaaaatttcg ctatgctcag 
               
               
                   
               
               
                  901 
                 gatgattttt ctctggatga aaatgaatgc cgagtcatga agggaaaccc atcagccaca 
               
               
                   
               
               
                  961 
                 gctggcccaa aggcatcccc aacacctcag aagacttcag ccaagagccc tggtcctatg 
               
               
                   
               
               
                 1021 
                 cgccgaagca agtctccagc tgactcagca aacggaacct ccagcagcca gctctctacc 
               
               
                   
               
               
                 1081 
                 cccaagtcta agcagtctcc catctctacg cccaccagtc ctggcagcct ccggaagcac 
               
               
                   
               
               
                 1141 
                 aaggacctgt acctgcctct gtccttggat gactcggact cgcttggtga ttccatgtaa 
               
               
                   
               
               
                 1201 
                 aggaggggag agtgctcaga gtccagagta caaatccaag cctatcattg tagtagggta 
               
               
                   
               
               
                 1261 
                 cttctgctca agtgtccaac agggctattg gtgctttcaa gtttttattt tgttgttgtt 
               
               
                   
               
               
                 1321 
                 gttattttga aaaacacatt gtaatatgtt gggtttattt tcctgtgatt tctcctctgg 
               
               
                   
               
               
                 1381 
                 gccactgatc cacagttacc aattatgaga gatagattga taaccatcct ttggggcagc 
               
               
                   
               
               
                 1441 
                 attccaggga tgcaaaatgt gctagtccat gacctttcaa tggaaagctt aggtgcctgc 
               
               
                   
               
               
                 1501 
                 gttatatttg ccctgtctaa ttttgcccat acagtcttcc ttctgtagag ggctgtttac 
               
               
                   
               
               
                 1561 
                 atatacagca cttaaaatgt ttgtgtggga aaaaaaaaac tcattggcag atccaagaat 
               
               
                   
               
               
                 1621 
                 gacaaacaca agtgcccctt ttctctggat ctcaagaatg gtggaggacc ctggaaggac 
               
               
                   
               
               
                 1681 
                 agcaaggcag ctccccagcc tcactcttca ctcctgattg aggcccgggt ttgttgtcca 
               
               
                   
               
               
                 1741 
                 gcaccaattc tggctgtcaa tggggagaaa taaaccaaca acttataatt gtgacaccag 
               
               
                   
               
               
                 1801 
                 atgcttagga tcctggtgct gggttagcta agagaataga cagaattgga aaatactgca 
               
               
                   
               
               
                 1861 
                 gacatttccg aagagtttat aaagcacagt gaattcctgg tcaatctctc cactgaggca 
               
               
                   
               
               
                 1921 
                 atttggaatc aataagcaat tgataatagt ttggagtaag ggacttcata tacctgattc 
               
               
                   
               
               
                 1981 
                 ctctagaagg ctgtctaaca taccacatga ttacatgaac tgtatggtat ccatctatct 
               
               
                   
               
               
                 2041 
                 ctgttctatt gaatgccttg ttaacagcca acactgaaaa cactgtgaga atttgttttc 
               
               
                   
               
               
                 2101 
                 aggtctgaca cctttcagtc tctttttata gcaagaaatc aatatccttt ttataaaaat 
               
               
                   
               
               
                 2161 
                 tcatgtctgt atttcaggag caaactcttc aggctccttt tttataaact ggtgattttt 
               
               
                   
               
               
                 2221 
                 cttttgtcta aaaaacacat gaagaaaatt taccaaaaaa aaaaaaaaaa gcagaagaat 
               
               
                   
               
               
                 2281 
                 aatgtagttt agaaattatg ctgtcactgc caaacagtaa cctccaggag aaaacaagat 
               
               
                   
               
               
                 2341 
                 gaatagcaga ggccaattca atagaatcag ttttttgata gctttttaac agttatgctt 
               
               
                   
               
               
                 2401 
                 gcattaataa tttcaatgtg gaccagacat tctaattata ttttaaatga aatgttacag 
               
               
                   
               
               
                 2461 
                 catattttaa gcaactcttt ttatctataa tcctaatatt tcatactgaa gacacagaaa 
               
               
                   
               
               
                 2521 
                 tctttcactt gtctttaaca ttagaaagga tttctcttta ctaaggactg atcatttgaa 
               
               
                   
               
               
                 2581 
                 atagttttca gtcttttgag atacaggttt ataacactgc tttttttttt ctgtaatcat 
               
               
                   
               
               
                 2641 
                 agcccataat ggcaaagaca actaaattta agtgaaggtc atgcatgcca attctgtgtt 
               
               
                   
               
               
                 2701 
                 tgcttttagc agatatgaag atttccttat ttctttgtaa ttgtgcagat attttgaaag 
               
               
                   
               
               
                 2761 
                 gcacagcatt cgaagccaag ctgctgtttg gctactgaat ggcttgcagt tgttcctcca 
               
               
                   
               
               
                 2821 
                 ctctaaatgg aatgagcttg ctgtgtgtgt gtgtggtggt ggtgggaggg ggtggtgcat 
               
               
                   
               
               
                 2881 
                 gtgtgtgtgt gtgtgtgcat ctgcagctgc ttcaaaatta ggaaatacta caggacaccc 
               
               
                   
               
               
                 2941 
                 ctgtaatgga ttggtggcaa ctgggtggca ctgctgatgt gcactgtgta ggggggaacc 
               
               
                   
               
               
                 3001 
                 cagtggtggt ggggtagctc agatgcccct agacaagctt cagatgtctg tagctaccag 
               
               
                   
               
               
                 3061 
                 aaacattttc ggttcaggaa aagtgagatg atggtagtac tggtttctgg tgaaattgaa 
               
               
                   
               
               
                 3121 
                 gaaccccaaa tgatgaggat ctctttttgc cccctctcct ttttttgtag acccattcaa 
               
               
                   
               
               
                 3181 
                 aaccattaat aagcccattt tactaagccc ctatttcttt ctagaagctc agggttttct 
               
               
                   
               
               
                 3241 
                 tagtgcctcc cagaacattt tgtagttaat tgggaaaaag tgatacttgg attagggggt 
               
               
                   
               
               
                 3301 
                 gtgggcataa agaatggtgg gaggcctgat tttaaacttc aggccagaac ccccaatgac 
               
               
                   
               
               
                 3361 
                 tccacccata gtctcacttt aggtctcatt tagtccatca cctttatttt aagttgagga 
               
               
                   
               
               
                 3421 
                 agtggaggct ggtaaagagc aggaccagag gaagaatcca gatttcctta tgcttgggcc 
               
               
                   
               
               
                 3481 
                 tcacactagc tctctgagta tttccttgat tgcggtatat gtactactag aaaataccaa 
               
               
                   
               
               
                 3541 
                 atggatatat tttctttagg ataacctttg aaccaacaat cttcaataac aatagtacat 
               
               
                   
               
               
                 3601 
                 cttccatctt acttttaatc gagtataagg aaatgtttct ttatggccat tttggaggga 
               
               
                   
               
               
                 3661 
                 gcaggggatg aggcttggca tagtccaaaa tttaagtctc caataattaa ttgcatttta 
               
               
                   
               
               
                 3721 
                 aattggccca ctttcaaggc aatttttttt gtgtgtctgt aactgagctc ctccacccct 
               
               
                   
               
               
                 3781 
                 gtcattcact tccaatttta cccaatccaa ttttagcact caagttccat tgtgttaatt 
               
               
                   
               
               
                 3841 
                 tctgcacggt caacaaacat caagtcagca agcatttgcc accactccct atacttctcc 
               
               
                   
               
               
                 3901 
                 ctccttctta cacacacaca cacacacaca cacacaatcc atctcttgct tgttcctacc 
               
               
                   
               
               
                 3961 
                 tcctgatttt tcttccctac agaaatagaa atagggacaa agaaggggaa aatgtatata 
               
               
                   
               
               
                 4021 
                 ttggggctgg gctgaacaac taacttcata agtagtatta actaggggta aattgagaga 
               
               
                   
               
               
                 4081 
                 aaagctcctt ttctcttcac tgttttggaa aggatagcca ttagcatgac tgctttgtgt 
               
               
                   
               
               
                 4141 
                 ccttatggac tttagtatta gcctagattg aattatagcg ttttctagct ggaaggaacc 
               
               
                   
               
               
                 4201 
                 ttaagatcac atcatctact cctctactcc aaatttctca ttcttcaggc caggaaaccg 
               
               
                   
               
               
                 4261 
                 agacacagag gtaaagtaat ttccccaagg tcacacagct ggctggggca ggattgggtt 
               
               
                   
               
               
                 4321 
                 tacaacccac atctcctggc tcttattcca gggccttttc ccactaagta gtattgcctt 
               
               
                   
               
               
                 4381 
                 ccattaggct cctgagagtt atttctcagg gtcatgttgc atcttggagc cacatgctgc 
               
               
                   
               
               
                 4441 
                 tgccctgatc tcagtgggaa atccacccag caacctaata cagccccttt tccctgcatt 
               
               
                   
               
               
                 4501 
                 cacctggttc ccatccacat gggttgcaga tgtccttgaa gagagtgagg cattgagggc 
               
               
                   
               
               
                 4561 
                 caataggagc aatggggtcc ctggccttgt ccatctgatt caggagatca ctgctccatc 
               
               
                   
               
               
                 4621 
                 gtgaggagcc ctctgaatag ccccccactg aatgcttgcc ttgcccaaat ggaatggagg 
               
               
                   
               
               
                 4681 
                 aagattgatt ttctccatca gttcaccttg tgtcatctca taatggttgg tctttccagg 
               
               
                   
               
               
                 4741 
                 ctgagggaaa tgtttcttgt ttccagagta gaaaaagaaa gagtggaaca atagctttgt 
               
               
                   
               
               
                 4801 
                 tcatcctaac tttctgagat ggcttttcaa cattttaaaa aaactagtgt ggctaccatt 
               
               
                   
               
               
                 4861 
                 cactggcaat gatttctttt agaatatggg agtaagatga gctagagaaa ataacctggt 
               
               
                   
               
               
                 4921 
                 ctcactgtgg ttgccctcat ccacaatgtc cccaaagcca tcctgctctg atgaggacaa 
               
               
                   
               
               
                 4981 
                 tttccaggta taagcaaggg gctttgtgac aaaaatgtac cctggctgat gttaaacatt 
               
               
                   
               
               
                 5041 
                 ggctcctgtg tttgcaccaa aatagcaagc tgtgtgctct atacactctt cccatcgtct 
               
               
                   
               
               
                 5101 
                 tgtgtacact gctcctgtgg ccttccacag cagaaaccag ggcaaaaggg tccaaacaca 
               
               
                   
               
               
                 5161 
                 tggttttcct tgctgcaagg ctcttcctgg gaactaaggg ggtatttatt agttcagttc 
               
               
                   
               
               
                 5221 
                 taagagacct ccttctgggc ttaccccact cctcaggtac ttctctctcc ttcctccttc 
               
               
                   
               
               
                 5281 
                 tcctccacag tcacaagtaa ccaaggaacc tgaaagtgga tgtgtagcta tttgaagaag 
               
               
                   
               
               
                 5341 
                 gcaaggaacc ctgagattct tctttgaatc ctctagtcca agtcttagac cagtgattgg 
               
               
                   
               
               
                 5401 
                 tgcttacctt gaacaaaatt ttgtctgtgt tcctaatccc ttcaatactc tgggtacaat 
               
               
                   
               
               
                 5461 
                 gctcccaatc accctgcaca tttgattcta aatggctttt attttttaaa aatccatatc 
               
               
                   
               
               
                 5521 
                 cctaggacaa gagaacagga tgcctatatc cccaaaatga gctccaggac actgatggga 
               
               
                   
               
               
                 5581 
                 atgatcccaa agatcacccc acctcagaaa cgtctgtgcc aagagacttc cccagataga 
               
               
                   
               
               
                 5641 
                 aacactggga cagtggtttg aacgacttct tttatggttg tccagtttgc tatggaaata 
               
               
                   
               
               
                 5701 
                 aaaggcattg attttttaaa aagatgattg gaacctgtct ttggccacat agggccactt 
               
               
                   
               
               
                 5761 
                 ggatccattt ccaggcctta ctcatatatt gccttcactg aagggctttg gctttaagtc 
               
               
                   
               
               
                 5821 
                 ccagactggt ctcccaagtg aaccataagt gttttggagc tcatctgggg tgaggcatga 
               
               
                   
               
               
                 5881 
                 gaatgttgcc ccatctatcc cttcaggaaa aggtgccttc cctccctttc tcctaaagcc 
               
               
                   
               
               
                 5941 
                 tggtccccag aaattgtttt tgtctccaaa agtctagtat ggtctttata cacccagact 
               
               
                   
               
               
                 6001 
                 cttagtgttg cgtcctgcct tgtttccttg ttaaggatct atgcagacct cccgctttgg 
               
               
                   
               
               
                 6061 
                 cttagctagc gtgacattgg ctatcatttg acaagactaa cttttttttt tttttttttt 
               
               
                   
               
               
                 6121 
                 tgactgagtc tccctctgtc acctaggctg gagtgcagtg gcacaatctt ggctcgctgc 
               
               
                   
               
               
                 6181 
                 aaccttcacc cttcacctcc caggtcgaag cgattctcct gcctcagtct cccgagtagc 
               
               
                   
               
               
                 6241 
                 tgggattaca ggcgtgcgcc accaaatctg gctatttttt tattattatt atttttagta 
               
               
                   
               
               
                 6301 
                 gagatggggt ttcaccatgt tggccagact ggtcttgaac tcttggcctc aaattatctg 
               
               
                   
               
               
                 6361 
                 cccacctcgg cctcccaaag tgctgggatt acaggcatga gccaccatgc ccagctgaca 
               
               
                   
               
               
                 6421 
                 agactaattt tttatccctt ggtttattgg cttcaacatc ttctggaatc agaggtgatt 
               
               
                   
               
               
                 6481 
                 ttttcttacc ttggatgcct gagactaggg gagtatagaa ttccaattgg taattaaggc 
               
               
                   
               
               
                 6541 
                 atctttctgc tcctgatcag aagggcaggt tagttgggag aggtcagatg gcacaacaga 
               
               
                   
               
               
                 6601 
                 agtcaccttg taagtaaggc aaagacttga aggcattagc gtttctcatt actaggtcaa 
               
               
                   
               
               
                 6661 
                 taacctgagg gaatcaatgg ctttttgccg ctctacctct tgtgtatctc tttgactttt 
               
               
                   
               
               
                 6721 
                 ctttctctgt ctagtttcct ctgttctcag tttatattct atgttatcag tctctctttc 
               
               
                   
               
               
                 6781 
                 cacagtacaa acatccatcc tttctcctgt gcaattctgt ctctccctct tattatcttt 
               
               
                   
               
               
                 6841 
                 atttgtactt tttccttcct ccctgtctag gcattgggca tgtgcctctt cttagcctgt 
               
               
                   
               
               
                 6901 
                 gattttgcct tgggactgat gataaattat ttccagattc aatcagccct ggtcctaccc 
               
               
                   
               
               
                 6961 
                 cagtccaatc agaagtatgt tggtgggaat caacctgatc ctggcccttt cttcttctcc 
               
               
                   
               
               
                 7021 
                 attttcattc gtaatccccc tcagcagatc tttacaagca gtttccttat agctcatgta 
               
               
                   
               
               
                 7081 
                 tctttaggtc tttgccttcc aagcactgta cagaatactt tgtggttcct ttttagtctg 
               
               
                   
               
               
                 7141 
                 acattttgtg gagcagtgaa gcgtgctcag agacataatc agctgaagag aaaaaatcca 
               
               
                   
               
               
                 7201 
                 cccatggatt tatatcagct aaatactaat aattgatttt gtttgatgtg cccataattt 
               
               
                   
               
               
                 7261 
                 ttaaagctgc aatataatat aatgagggac cacaggtaat ttctcctgtc atttgttttg 
               
               
                   
               
               
                 7321 
                 gctggatggg ggtgggggag taattgctta aagttttacc attacacatt aaactctcta 
               
               
                   
               
               
                 7381 
                 taataatctt gtttggggct tgctaactgt tgagctgttt taactaaact ggtaggcaat 
               
               
                   
               
               
                 7441 
                 cggagttgat ttaaatgaaa agataattta acaaatctat actataaaaa gagacatttg 
               
               
                   
               
               
                 7501 
                 cttaattgac atgtattttt tccttctgag tcacctaaac atttactctt gacaccaact 
               
               
                   
               
               
                 7561 
                 gttcatgata ctgaatagac agtccatata agagaaatta gtggacctaa agaagccaga 
               
               
                   
               
               
                 7621 
                 ttgtaggtgt taatttatta aacagagtgc aaagcccttg gaaatgtcac tgcttggcaa 
               
               
                   
               
               
                 7681 
                 taccatatgg aatgccaaaa tttacaatga cttttcttta taagttatcc aaaagggatt 
               
               
                   
               
               
                 7741 
                 tgaacaagta agaggttatg ccaaaatgtc tccaatgtat ggtcctgtaa tatattgcag 
               
               
                   
               
               
                 7801 
                 cttgaagcca atgatccctt atgacttgta tacaactaat gcatgtttta ttgaattttg 
               
               
                   
               
               
                 7861 
                 catttcccac gtgtggtaag ttctttaaaa tgtttttgat cacctttttg tgccattaaa 
               
               
                   
               
               
                 7921 
                 cttgtacaga aaatgttttt atggccattt tcaaagggag aaagtttaaa atggaaacag 
               
               
                   
               
               
                 7981 
                 cccacccttt ctgccctata gctgtagtta gaattgagta cctgtagcaa aacagctgta 
               
               
                   
               
               
                 8041 
                 attggtggtt gtagtgttag aggtgttagc ttgctagtga ctagctttgg agagtaaatg 
               
               
                   
               
               
                 8101 
                 catggtattg tacatcacat ttcttaactc gttttaacct ctgaaaagaa tatattcttc 
               
               
                   
               
               
                 8161 
                 tttgtagtcc ttcttcccac ccccttgccc tctccctctc cctgctccca gttgtcttac 
               
               
                   
               
               
                 8221 
                 agttgtaaat atctgatttg aggcccaata actcttgcca agtaaagtca gcaaacaaca 
               
               
                   
               
               
                 8281 
                 aacaaaccaa aatgtgggga aaaggcattt ctcaaccatc tctcagcagt tattgatcat 
               
               
                   
               
               
                 8341 
                 ttcttaagga acagcattgt gatcaaagac tcaactttac gtaaaaatca gtggtaaatt 
               
               
                   
               
               
                 8401 
                 ggggttgtat ttggccattt gattacattt caggattgaa tagttttcag aatcacatgt 
               
               
                   
               
               
                 8461 
                 aatccaaaga cagtaggtag tgatgtccct tatccctgca gctgttttaa gatagagacc 
               
               
                   
               
               
                 8521 
                 tcagaagact ctgcttgacc gatgaccaat aattatttga aaaaaaaaga aaaaatgaga 
               
               
                   
               
               
                 8581 
                 gaaataaaac agatatttaa gaactttagc cacctattta gaatagttat agccagaaaa 
               
               
                   
               
               
                 8641 
                 aaaaacaagg gcatgagttc aaatgcatta ctatcagtgt cctaggcaat acctaaccta 
               
               
                   
               
               
                 8701 
                 ctctgaaatt gtgattcaaa agcagtattt caagaggcat tctccttttt tggtttgctg 
               
               
                   
               
               
                 8761 
                 accccacttg gactggtagg tttggtgagg cccccataaa ccagctggag cagacccttt 
               
               
                   
               
               
                 8821 
                 tcatctcctg tgcctgtaac acccctcttc ccccaccccc tccgcaattc aatgagggct 
               
               
                   
               
               
                 8881 
                 ttcttgggtc agaggacttc aaggttgtct agagaagttt gccatgtgtg taaggtgctg 
               
               
                   
               
               
                 8941 
                 tgaactgtga gtgctgaaga ttcgcagcat tcaataccag gcagccaaag agctgctctt 
               
               
                   
               
               
                 9001 
                 gcaattattt tggctctcaa gctctgttct tcatcgcatt ctcatttctg tgtacatttg 
               
               
                   
               
               
                 9061 
                 caagatgtgt gtaatgtcat tttccaaaaa taaaatttga tttcaataaa aaaaaaaaaa 
               
               
                   
               
               
                 9121 
                 aaaaaaaaaa aaaaa 
               
            
           
         
       
     
     By “GABRA1” (or gamma-aminobutyric acid (GABA) A receptor) is meant a polypeptide or fragment thereof having at least about 85% amino acid identity to NCBI Accession No. AAH30696.1. 
     
       
         
           
               
            
               
                 (SEQ ID NO: 69) 
               
               
                 MRKSPGLSDCLWAWILLLSTLTGRSYGQPSLQDELKDNTTVFTRILDRLL 
               
               
                   
               
               
                 DGYDNRLRPGLGERVTEVKTDIFVTSFGPVSDHDMEYTIDVFFRQSWKDE 
               
               
                   
               
               
                 RLKFKGPMTVLRLNNLMASKIWTPDTFFHNGKKSVAHNMTMPNKLLRITE 
               
               
                   
               
               
                 DGTLLYTMRLTVRAECPMHLEDFPMDAHACPLKFGSYAYTRAEVVYEWTR 
               
               
                   
               
               
                 EPARSVVVAEDGSRLNQYDLLGQTVDSGIVQSSTGEYVVMTTHFHLKRKI 
               
               
                   
               
               
                 GYFVIQTYLPCIMTVILSQVSFWLNRESVPARTVFGVTTVLTMTTLSISA 
               
               
                   
               
               
                 RNSLPKVAYATAMDWFIAVCYAFVFSALIEFATVNYFTKRGYAWDGKSVV 
               
               
                   
               
               
                 PEKPKKVKDPLIKKNNTYAPTATSYTPNLARGDPGLATIAKSATIEPKEV 
               
               
                   
               
               
                 KPETKPPEPKKTFNSVSKIDRLSRIAFPLLFGIFNLVYWATYLNREPQLK 
               
               
                   
               
               
                 APTPHQ 
               
            
           
         
       
     
     By “GABRA1 polynucleotide” (or gamma-aminobutyric acid (GABA) A receptor) is meant a polynucleotide encoding an GABRA1 polypeptide. An exemplary GABRA1 nucleic acid molecule (e.g., mRNA) is provided at NCBI Accession No. BC030696. 
     
       
         
           
               
               
            
               
                 (SEQ ID NO: 70) 
                   
               
            
           
           
               
               
               
            
               
                    1 
                 agcggagcgg gcgagcaagg gagcgagcag gacaggagcc tgatcccaca gctgctgctc 
                   
               
               
                   
               
               
                   61 
                 cagcccgcga tgaggaaaag tccaggtctg tctgactgtc tttgggcctg gatcctcctt 
               
               
                   
               
               
                  121 
                 ctgagcacac tgactggaag aagctatgga cagccgtcat tacaagatga acttaaagac 
               
               
                   
               
               
                  181 
                 aataccactg tcttcaccag gattttggac agactcctag atggttatga caatcgcctg 
               
               
                   
               
               
                  241 
                 agaccaggat tgggagagcg tgtaaccgaa gtgaagactg atatcttcgt caccagtttc 
               
               
                   
               
               
                  301 
                 ggacccgttt cagaccatga tatggaatat acaatagatg tatttttccg tcaaagctgg 
               
               
                   
               
               
                  361 
                 aaggatgaaa ggttaaaatt taaaggacct atgacagtcc tccggttaaa taacctaatg 
               
               
                   
               
               
                  421 
                 gcaagtaaaa tctggactcc ggacacattt ttccacaatg gaaagaagtc agtggcccac 
               
               
                   
               
               
                  481 
                 aacatgacca tgcccaacaa actcctgcgg atcacagagg atggcacctt gctgtacacc 
               
               
                   
               
               
                  541 
                 atgaggctga cagtgagagc tgaatgtccg atgcatttgg aggacttccc tatggatgcc 
               
               
                   
               
               
                  601 
                 catgcttgcc cactaaaatt tggaagttat gcttatacaa gagcagaagt tgtttatgaa 
               
               
                   
               
               
                  661 
                 tggaccagag agccagcacg ctcagtggtt gtagcagaag atggatcacg tctaaaccag 
               
               
                   
               
               
                  721 
                 tatgaccttc ttggacaaac agtagactct ggaattgtcc agtcaagtac aggagaatat 
               
               
                   
               
               
                  781 
                 gttgttatga ccactcattt ccacttgaag agaaagattg gctactttgt tattcaaaca 
               
               
                   
               
               
                  841 
                 tacctgccat gcataatgac agtgattctc tcacaagtct ccttctggct caacagagag 
               
               
                   
               
               
                  901 
                 tctgtaccag caagaactgt ctttggagta acaactgtgc tcaccatgac aacattgagc 
               
               
                   
               
               
                  961 
                 atcagtgcca gaaactccct ccctaaggtg gcttatgcaa cagctatgga ttggtttatt 
               
               
                   
               
               
                 1021 
                 gccgtgtgct atgcctttgt gttctcagct ctgattgagt ttgccacagt aaactatttc 
               
               
                   
               
               
                 1081 
                 actaagagag gttatgcatg ggatggcaaa agtgtggttc cagaaaagcc aaagaaagta 
               
               
                   
               
               
                 1141 
                 aaggatcctc ttattaagaa aaacaacact tacgctccaa cagcaaccag ctacacccct 
               
               
                   
               
               
                 1201 
                 aatttggcca ggggcgaccc gggcttagcc accattgcta aaagtgcaac catagaacct 
               
               
                   
               
               
                 1261 
                 aaagaggtca agcccgaaac aaaaccacca gaacccaaga aaacctttaa cagtgtcagc 
               
               
                   
               
               
                 1321 
                 aaaattgacc gactgtcaag aatagccttc ccgctgctat ttggaatctt taacttagtc 
               
               
                   
               
               
                 1381 
                 tactgggcta cgtatttaaa cagagagcct cagctaaaag cccccacacc acatcaatag 
               
               
                   
               
               
                 1441 
                 atcttttact cacattctgt tgttcagtcc tctgcactgg gaatttattt atgttctcaa 
               
               
                   
               
               
                 1501 
                 cgcagtaatt cccatctgct ttattgcctc tgtcttaaag aatttgaaag tttccttatt 
               
               
                   
               
               
                 1561 
                 ttcataattc atttaagaac aagagacccc tgtctggcag tctggagcaa agcagactat 
               
               
                   
               
               
                 1621 
                 gcagcttgga gacaggattc tgacagagca agcgaaagag caaagtcatg tcagaaggag 
               
               
                   
               
               
                 1681 
                 acagaatgag agagaaaaga gggggaagat ggttcaaaga tacaagaaaa agtagaaaaa 
               
               
                   
               
               
                 1741 
                 aaaataacac ttaactaaaa cccctaggtc atttgtagat atatatttcc aaatattcta 
               
               
                   
               
               
                 1801 
                 aaaaagatac tgtatatgtc aaaaatattt ttatgtgaag gtgtttcaaa gggtaaatta 
               
               
                   
               
               
                 1861 
                 taaatgtttc atgaagaaaa aattttaaaa atctacgtct ttattacaca aactatggtg 
               
               
                   
               
               
                 1921 
                 tgcttatgtt tttgttttgc tttttaaact gatgtatagc tttaacattt tgtttccaaa 
               
               
                   
               
               
                 1981 
                 gctgaagatc cccattcttt ctctttgaaa aaaaaaaagg cctaatgcat tattttgtca 
               
               
                   
               
               
                 2041 
                 taaaatgcta ttttaaaatt catggaactt tcatacgtaa aggtgcagtt gctcattgta 
               
               
                   
               
               
                 2101 
                 gagcacattt agtccaatga agataaatgc tttaaatagt ttacttcact ttcatctgag 
               
               
                   
               
               
                 2161 
                 cttttaccac tagactcaag gaagaataat tttaacagac atgtatactc catagaaact 
               
               
                   
               
               
                 2221 
                 aaattaaaat agtttaaaaa tattcccttt ttcaccctat tttcagatag cacatgagcc 
               
               
                   
               
               
                 2281 
                 caacactcac ttaattctca ttatgaagat gtttttagag gggcaaaaat attttgcaag 
               
               
                   
               
               
                 2341 
                 ctctggaatt gttgaatgta ttcttttata taactacatt aaaagcttta gattgaaatt 
               
               
                   
               
               
                 2401 
                 tatgactagc aaacaaaaat agaatatata aacgatatat gtaaatatac agcatgagat 
               
               
                   
               
               
                 2461 
                 tgtacatttt ttactttttt aaaattgtgt tcttaaaata ttgtgtaaga atcactgcac 
               
               
                   
               
               
                 2521 
                 ttagctgttg gaatgttgtt aaatgctatg gaaatacatt tagaacctgc atttaagaac 
               
               
                   
               
               
                 2581 
                 agaacagcaa gtatgaacca catggaactt aaaacatatg ggtgtgaagt ccacttatgt 
               
               
                   
               
               
                 2641 
                 agacaaaact tataatttcc aaactgttgt ctagtataca gtgatcagtt gctctctgtt 
               
               
                   
               
               
                 2701 
                 caagtcattc cacacatttc cctattttag gctattataa tatagaaaga aaatgggaag 
               
               
                   
               
               
                 2761 
                 cattagttgg agctagaaaa tgaactgtat attattgcta tatttgctaa taccaactat 
               
               
                   
               
               
                 2821 
                 ttcaataagt gttgtaccat atgtagcatt aaatataaaa tacataaaag aatgtacaga 
               
               
                   
               
               
                 2881 
                 aaatagcttt tattgagtaa tattacattt catttatact gtagcaatat atttgtaggt 
               
               
                   
               
               
                 2941 
                 atactatgta agggctttaa ataaaagagg tccattaata cttccttata aaaattctag 
               
               
                   
               
               
                 3001 
                 tctgtttcat tactgcccag atgttttaga gataaatatt tatgcagaag gtatttttga 
               
               
                   
               
               
                 3061 
                 agtctccttt tgtctgatag agtttaacag atatttaaat ttagtgctca gaatccacaa 
               
               
                   
               
               
                 3121 
                 gtcacggtct aaacacactt agaatactac agcataaatc tgttagcatt attgccaaat 
               
               
                   
               
               
                 3181 
                 aagacagttg ggatccaaac ccaagtcttg agcaatgttt ttctcaaaaa gctgctatcc 
               
               
                   
               
               
                 3241 
                 aatgatatag gaaaatacat tgtgttttcc taaacacact tttcttttta aatgtgcttc 
               
               
                   
               
               
                 3301 
                 attgtttgat ttggtcctgc ctaaatttca caagctaggc caatgaaggc tgaatcaaag 
               
               
                   
               
               
                 3361 
                 acatttcatc caccaatatc atgtgtagat attatgtata gaaaataaaa taaattatgg 
               
               
                   
               
               
                 3421 
                 ctccaaaaaa aaaaaaaaaa 
               
            
           
         
       
     
     Other features and advantages of the invention will be apparent to those skilled in the art from the following detailed description and claims. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The patent or applicatin file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings will be provided by the Office upon request and payent of the necessary fee. 
         FIGS.  1 A- 1 D  depict characterization of BMPS during differentiation.  FIG.  1 A  depicts a diagram of a differentiation protocol.  FIG.  1 B  depicts size of aggregates measured during the 3D neuronal differentiation. Negative days on the x-axis represent 3D cells cultured in NPC medium while positive days represent 3D cells cultured in differentiation medium. FIG.  1 C 1 -C 5  depicts BMPS mRNA and miRNA expression of different markers during differentiation.  FIG.  1 D  depicts flow cytometry population analysis of BMPS at different stages of differentiation. 
         FIGS.  2 A- 2 C  depict morphological characterization of BMPS.  FIG.  2 A  depicts co-immunostaining of neurons with markers. MAP2+ neurons were co-immunostained with the maturation marker Nestin at 2, 4, and 8 weeks of differentiation, which showed progressive increase of MAP2+ neurons and decrease of Nestin+ cells over time (panels a, b, c), demonstrating neuronal maturation. Co-immunostaining of neurons (NF-H) with the myelin marker MBP at 2, 4, and 8 weeks of differentiation (d,e,f, respectively) showed progressive increase of MBP+ cells in association with axonal processes. An increasing number of MBP+ cells (oligodendrocytes) was observed in association with axons (panels d, e, f).  FIG.  2 B  depicts neuronal and glial cell diversity was evaluated at 8 weeks. Neurons (MAP2, NF, SYP and SMI32) were visualized interacting with glia (GFAP and NOGOA). Neurons disclosed characteristic perykaria, dendrites (MAP2, panels a, b) and axons (NF, SMI32, panels c-f) associated with glia. Neurons exhibited diverse neurotransmitter identities shown by identification of glutamatergic VGLUT1+ (panels g, h), GABAergic CALB+(panels i, j) and dopaminergic TH (panels k, 1) neurons.  FIG.  2 C  depicts that GFAP+ astroglia and CNPase+, O1+ and MBP+ oligodendroglia were identified. Oligodendroglia appeared mixed among astrocytes (panels a, b). O1+ (panels c, d) and MBP+ (panels e, f) oligodendrocytes were associated with axonal processes. Astrocytes established relationships with oligodendrocytes and exhibited characteristic multipolar processes (panels g, h). MBP+ oligodendrocytes issued processes in association with axons (panel i) 3D-reconstruction demonstrated myelinating processes resembling human myelination (panels j, k). Electron microscopy analysis of BMPS at 4 and 8 weeks of differentiation identified morphology of axonal structures and cells (e.g., oligodendrocytes) (panel 1). Myelinating-like processes, which closely resembled cross-sections of myelinated axons of the CNS were identified at 8 weeks of differentiation (panel m).  FIG.  2 D  depicts MBP+ oligodendrocytes issued processes in close association with axons and seemed to enwrap them at 8 weeks (a,b,c). Myelination calculated as the mean percentage MBP positive oligodendrocyte processes coverage of NF-H-positive axons (a,b,c) at 2, 4 and 8 weeks in at least 2 independent experiments showed significant increase of myelination observed with time of differentiation (p&lt;0.001) (d).  FIG.  2 E  depicts 3D-reconstruction based on confocal z-stacks at 8 weeks demonstrating a “wrapping” myelinating process, which resembled the myelination of axons in human CNS.  FIG.  2 F  depicts a comparison of expression of neuronal and glial markers at 2 and 8 weeks. At 2 weeks, oligodendrocytes (O1, CNPase, NOGOA) were identified without a preferential localization (a,b,e,f,i,j), later they resemble human oligodendrocytes and localize in close proximity with axons (c,d, g,h, k,l). At 2 weeks there are few MAP2-positive cells without identifiable neuronal shape (I,j) whereas at 8 weeks, the MAP2+ cells acquire a well-defined dendritic network (k,l). The amount of astrocytes and density of the astroglial network increases with time of differentiation (GFAP, g,h).  FIG.  2 G  depicts variation in the nuclear morphology. Co-immunostaining of neurons (MAP2) with cell-division marker KI67 showed that some cells are dividing (a,b), there was also a small degree of apoptosis demonstrated by positive staining with CASP3 (c). CASP 3-positive nuclei did not co-localize with mature neurons (d).  FIG.  2 H  depicts ultrastructure analysis by electron microscopy of 4 week BMPS showed evidence of cell to cell junctions demonstrating functional interactions between the cells (arrows, a,b). Nuclear variation was confirmed by the presence of a few apoptotic nuclei (c) and normal healthy nuclei (d). NF: Neurofilament-heavy-chain, MAP2: Microtubule-associated-protein 2, MBP: myelin-basic-protein, VGLUT1: Vesicular-glutamate-transporter 1, GFAP: Glial-fibrillary-acidic-protein, CALB: Calbindin, NOGOA: Neurite-outgrowth-inhibitor, SYP: Synaptophysin, SMI32: Nonphosphorylated-neurofilament, TH: Tyrosine-hydroxylase, O1: Olig1, CNPase: 2′,3′-Cyclic-nucleotide-3′-phosphodiesterase. Scale Bar: 10 μm. 
         FIGS.  3 A- 3 F  depict electrical activity of BMPS. Cells were cultured in 3D for 8 weeks and then cultured in 12-well and 48-well MEA plates for 4 more weeks.  FIG.  3 A  depicts heat map recordings from a 48-well plate.  FIG.  3 B  depicts illustration of an active well showing spike morphology and  FIG.  3 C  depicts spike activity.  FIGS.  3 D and  3 E  depicts phase-contrast imaging of the mini-brains on MEAs, electrode diameter is 40-50 μm and inter-electrode space is 350 μm.  FIG.  3 F  depicts activity pattern recordings over 0.05 spikes/sec of the electrode over 10 min. 
         FIGS.  4 A- 4 G  depict Parkinson&#39;s disease (PD) application of BMPS. BMPS were differentiated for 4 weeks and exposed to rotenone and MPP+ for 12 and 24 hours.  FIG.  4 A  depicts viability (resazurin assay) of BMPS after 24 hours rotenone exposure.  FIG.  4 B  depicts ROS (OxiSelect™ In Vitro ROS/RNS Assay Kit) production of BMPS after 12 and 24 hours rotenone exposure.  FIG.  4 C  depicts viability (resazurin assay) of BMPS after 24 hours MPP+ exposure.  FIG.  4 D  depicts ROS (OxiSelect™ In Vitro ROS/RNS Assay Kit) production of BMPS after 12 and 24 hours MPP+ exposure.  FIGS.  4 E and  4 F  depict confocal images of BMPS exposed to different concentrations of rotenone and MPP+ for NF200 (Red), TH (Green) and Hoechst nucleus staining (Blue).  FIG.  4 G  depicts expression of genes associated with oxidative stress and PD by real time RT-PCR. Graphs represent the relative expression of different markers compared to control (cells not treated) after 24 hours exposure to 5 μM rotenone and 1 mM MPP+. Genes of interest: mitochondrial complex 5 (ATP50, ATP5C1), mitochondrial complex 1 (NDUFB1), oxidative stress (KEAP1) and genes related to PD (TH, SNCA, TBR1, CASP1). Data are presented as mean±SD, of 3 independent experiments performed in 3 replicates. *P&lt;0.05 comparing to control (untreated). 
         FIGS.  5 A- 5 D  depict Down&#39;s Syndrome application of BMPS. BMPS were produced with iPSCs derived from a patient with Down&#39;s Syndrome.  FIG.  5 A  depicts morphological characterization with immunostaining of neurons (MAP2, Syn1, TH, SYP), neural precursor cells (nestin) and glial cells (GFAP) at 8 weeks of differentiation.  FIG.  5 B  depicts expression of genes in healthy BMPS vs. Down&#39;s Syndrome BMPS before and after treatment with 5 μM rotenone, after 24 hours exposure. Genes of interest include CNS markers (TH, OLIG2, NEFH), mitochondrial markers (ATP5C1, ATP5J, ATP50) and ROS markers (NFE2L2, SOD1) which were measured by comparing control with exposed cells to rotenone on both healthy and Down syndrome derived mini-brains.  FIGS.  5 C and  5 D  depict karyotyping of iPSCs derived from the patient with Down&#39;s Syndrome. aCGH+SNP results for Down syndrome iPSC line are shown. 
         FIG.  6    depicts viability of pre-frozen NT2 human teratocarcinoma cell line and iPSC derived mini-brains. Fmedium corresponds to 95% FBS and 5% DMSO. NPC fmedium corresponds to STEMdiff™ Neural Progenitor Freezing Medium. Viability was measured by resazurin cell viability assay. Non-frozen cells at the same stage of differentiation were used as control aggregates. 
         FIG.  7    depicts an example of a BMPS covered with other cell types. LUHMES fluorescent cells (red) were incorporated to a BMP using gravity systems to cover the surface of the aggregate. 
         FIGS.  8 A- 8 E  depict morphologic characterization of mature human BMPS.  FIG.  8 A  shows at 8 weeks, neuronal populations exhibited a diversity of neurotransmitter identities as shown by identification of dopaminergic TH+ (a,b), glutamatergic VGLUT1+ (c,d) and gabaergic calbindin+ (e,f) neurons. Neurons disclosed characteristic axons (NF) and synaptic proteins (SYN) (g,h).  FIG.  8 B  depicts two distinctive glial populations were identified in close interaction with neuronal populations, GFAP+ astroglia and CNPase+, O1+, NOGOA+ oligodendroglia. O1+ oligodendrocytes were closely associated with axonal processes (NF) (a,b), CNPase+ oligodendroglia appeared mixed among GFAP+ astroglia (c,d) and exhibited the characteristic multipolar glial processes, which extended from the perykaria (e,f). NOGOA+ cells were associated with MAP+ neurons (g,h).  FIG.  8 C  depicts example of custom algorithm created using the Cellomics Target Activation image-analysis software package to study astrocytes and oligodendrocytes (a,b,c,d). Quantification of cell populations as a percentage of the total nuclei count showed 3% NOGOA+ positive cells, 9% CNPase+ cells and 19% GFAP+ cells at 8 weeks (e).  FIG.  8 D  shows Co-expression of mature oligodendroglia markers (MBP and O2).  FIG.  8 E  shows expression of neuronal markers (VGLUT, TUJ1, SYN). Scale Bar: 10 μm. 
         FIGS.  9 A- 9 D  depict the generation of microglia-containing BS (μBS). Immortalized Huma Microglia—SV40 were incorporated to 7 week differtiated BS by gravity.  FIG.  9 A  shows a diagram of μBS generation procedure under one embodiment.  FIG.  8 B  provides a comparison between μBS and BS using different microglia markers (TMEM119, Mertk, Axl) and hematoxylin/eosin (HE).  FIG.  9 C  provides confocial images of immunohistochemistry for the microglia marker IBA1 (green), the neuronal marker NF200 (red) and nuclear staining (Hoechst 33342, blue) in μBS. 48 h after microglia incorporation.  FIG.  9 D  shows details of microglia aggregations in μBS. Green arrow indicated microglia cluster and red arrow indicates the BS. Bars represent 100 μm ( FIG.  9 B ),m ( FIG.  9 C , upper panel), 20 μm ( FIG.  9 C , all other panels), and 50 μm ( FIG.  9 D ). 
         FIGS.  10 A- 10 C  depicts differences between BS, μBS, and microglia after LPS treatment. The microglia, BS, μBS, were exposed to 20 ng/mL LPS up to 24 h.  FIG.  10 A  shows gene expression of IL6, IL10, IL1b, CCL2, and TNFa after LPS treatment on the different models (BS, μBS, and microglia cells). Data are shown as fold change of treated versus untreated up to an hour post treatment (3, 6, 12 and 24 h after treatment).  FIG.  10 B  shows changes in cell cycle in percentage of the cells in G2 plus S phase in microglia cells, BS and μBS treated or non-treated with LPS. Each dot symbol represents a replicate sample of (N+3).  FIG.  10 C  shows Annexim V Apoptosis Muse assay. Results show % live cells microglia, as μBS cells treated (+) or not treated (−) with LPS. Each symbol represent a replicate (n=3). Statistical analysis in  FIG.  10 A  was performed using Dunnett test on ΔΔCt. The asterisks symbols represents *P &lt; 0.05 and **P &lt; 0.01 (two independent experiments and three boilogical replicates on each experiment). 
         FIG.  11    shows virus infection by immunohistochemistry in BrainSpheres with μBS) and without microglia (BS). Green represents the Flavivirus marker for ZIKY ( NSI ) and DENV-L redrepresents microglia markers IBA 1  abd NF200. Bard represent 50 μM (lower magnification) and 10 μm (higher magnification) 
         FIGS  12 A- 12 D  depict the effects of Flavivirus infection on 3D human iPSC-derived brain spheres (BrainSpheres, BS) without ot with microglia cells (μBS). The microglia cells, BS, and μBS wereinfected wirt Debgue, ZIKV-BR abd ZIKV-UG using MOI equal 0.1.  FIG.  12 A  shows the growth kinetics of flaviviruses over time for the three models. The viral load (RNA ccopies/mL) are shown with standard deviation.  FIG.  12 B  depicts changes in cell cycle shown as percentage of cells in G2/S phase in BS, μBS, and microglia treated or non-treated with the different viruses,  FIG.  12 C  shown Annexin V Apoptosis Muse assay results. Results represent % live cells in BS, μBS, and microglia samples after the different flavivirus treatments.  FIG.  12 D  shows gene expression relatvive quantification for TNFα, CCL2, and IL-6 over the time. Statistical analysis was performed using the Dunnett&#39;s Test (*mean eqqual p &lt;0.05 and **P &lt;0.01) for two independent experiments, three biological replicates on each experiment. 
         FIGS  13 A- 13 C  show an alternative protocol performed to incorporate microglia into BS 3D cultures. When NPC 3  reaches 95% confluence, 1 / 10 6  microglia were added to the flask. After 24 h, the co-culture was detached mechanically with a cell scraper (Sarstedt, Newton, NC, United States, 2-position, Blade 25, 83.1830), re-pipetted for disaggregation, and counted using Countless Automated Cell Counter (Invitrogen, Carlsbad, CA, United States), 2+10 6  cells per well were then plated in non-treated 6-well plates and cultures as BS for 8 weeks. The dendity was chosen to have approximately 10% microglia cells.  FIG.  13 A  shows a diagrammatic representation for the alternative protocol. 
         FIG  13 B  is immunohistochemistry showing microglia marker (IBA1) and neuronal marker (NF200).  FIG.  13 C  shows immunohistopathology characterization of the microglia incorporation for this method of μBS generation markers are meentioned in Example. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention is based, at least in part, upon the discovery that brain microphysiological systems (BMPS) can be produced from induced pluripotent stem cells (iPSCs). Furthermore, the invention provides for reproducible BMPS that differentiate into mature neurons and glial cells (astrocytes and oligodendrocytes) in the central nervous system. This model is spontaneously electrophysiological active and may be reproduced with patient or genetically modified cells. The derivation of 3D BMPS from iPSCs has applications in the study and treatment of neurological and neurodevelopmental diseases. In some embodiments, the present disclosure provides for compositions and methods to study and/or treat neurodevelopmental and neurodegenerative disorders. In some cases, the neurodevelopmental and neurodegenerative disorders treated and/or studied by the present disclosure include, but are not limited to, autism, encephalitis, trauma, brain cancer, stroke, Amyotrophic lateral sclerosis, Huntington&#39;s Disease, muscular dystrophy, neurodegenerative disorder, neurodevelopmental disorder, Multiple Sclerosis, infection, Parkinson&#39;s Disease and Alzheimer&#39;s Disease. 
     As described herein, the present disclosure provides for the derivation of a multitude of identical brain microphysiological systems (BMPS) from stem cells, preferably of human origin, but including stem cells from animal origin. The preferred starting material are human induced pluripotent stem cells or embryonic stem cells, although other pluripotent stem cells such as, for example, neuronal precursor cells and mesenchymal stem cells may also be employed. Human in-vitro models of brain neurophysiology are needed to investigate molecular and cellular mechanisms associated with neurological disorders and neurotoxicity. The techniques herein provide a reproducible iPSC-derived human 3D BMPS that includes differentiated mature neurons and glial cells (astrocytes and oligodendrocytes) that reproduce neuronal-glial interactions and connectivity. BMPS mature over about eight weeks and show the critical elements of neuronal function including, but not limited to, synaptogenesis and neuron-to-neuron (e.g. spontaneous electric field potentials) and neuronal-glial interactions (e.g. myelination). Advantageously, the BMPS described herein include mature neurons (e.g., glutamatergic, dopaminergic and GABAergic neurons) and glial cells (e.g., astrocytes and oligodendrocytes). Quantification of the different cell types exhibited high reproducibility between experiments. Moreover, the BMPS disclosed herein present neuron and glial functions such as spontaneous electrical activity and axon myelination. The BMPS described herein are able to mimic the microenvironment of the central nervous system, which is a significant advance in the field of neurobiology as this ability has not been achieved at this level of functionality, reproducibility, and consistency in prior art in vitro systems. 
     In particular, the high amount of myelination of axons (up to 40%) in the disclosed BMPS represents a significant improvement over the prior art. Myelin pathology is a rather frequent condition in demyelinating and inflammatory disorders such as multiple sclerosis and post-infection diseases as well as other neurological diseases such as acute and post-traumatic brain injury, stroke and neurodegenerative disorders (see e.g., Fumagalli et al., 2016; Tse and Herrup, 2016). Moreover, the myelination process can be perturbed by exposure to chemicals and drugs (see e.g., Garcia et al., 2005; Brubaker et al., 2009; Creeley et al., 2013) during brain development and adulthood. For example, the BMPS disclosed herein show 40% overall myelination after 8 weeks of differentiation. Myelin was observed by immunohistochemistry and confirmed by confocal microscopy 3D reconstruction and electron microscopy. These findings are of particular relevance since myelin is crucial for proper neuronal function and development. The ability to assess oligodendroglia function and mechanisms associated with myelination in this BMPS model provide an excellent tool for future studies of neurological disorders such as multiple sclerosis and other demyelinating diseases. Thus, the BMPS provides a suitable and reliable model to investigate neuron-neuroglia function in neurotoxicology or other pathogenic mechanisms that has heretofore not been available in the prior art. 
     The method disclosed combines gyratory shaking or regular stirring and the addition of growth factors to obtain the basic model. Suitable conditions as to how to achieve reproducible brain composition are disclosed herein. In contrast to earlier models, identical units of BMPS are produced, which allow comparative testing for the purpose of product development or safety assessments. 
     According to the techniques herein, a number of additional measures complement the basic BMPS to increase their completeness in modeling the human brain and improve its usefulness for such testing, for example: 
     1. The addition of microglia: All stem-cell-derived brain models described so far lack micro-glia. The techniques herein provide that the addition of micro-glia precursor cells and suitable growth factors may allow microglia to be added to the model. Suitable cells may be monocytes (e.g., human monocytes), hematopoetic stem cells, respective (pro-)monocyte cell lines, and isolated microglia. 
     2. The addition of a blood-brain-barrier: The human brain is protected by a tight blood-brain-barrier that excludes many substances from the brain. For the first time, the techniques herein provide a method to form a blood-brain-barrier to the BMPS via cells such as, for example, human endothelial cells. 
     3. Addition of reporter and reporter cells: During the generation of the BMPS, cells carrying reporter for testing purposes may be used or added. These include, but are not limited to, fluorescent or luminescent markers to indicate a certain cell lineage or cell response. Genetic transient or permanent transfections are the primary, but not only, method of choice. 
     4. The BMPS may also be produced, entirely or in its components, from cells from a specific genetic background, e.g. from patients with a specific disease or after selective genetic manipulation of the cells. 
     5. The versatility of the BMPS may be improved by combining it with electrodes including, but not limited to, micro-electrode arrays (MEA). 
     6. The versatility of the BMPS may be improved by combining it with other MPS (organ models) platforms such as, for example, microfluidic human-on-chip systems, perfusion chambers and others. 
     7. Transportability of BMPS: Methods to cryopreserve BMPS were developed, which allow transport to other laboratories and testing or integration into multi-MPS platforms. 
     Simplified neural in vitro systems do not reflect physiology, interactions between different cell types, or human genetics. Induced pluripotent stem cells (iPSC)-derived human-relevant microphysiological systems (MPS) better mimic the organ level, but are too complex for chemical and drug screening. As described herein, a reproducible 3D brain MPS (BMPS) that differentiates into mature neurons and glial cells (astrocytes and oligodendrocytes), which reproduces the topology of neuronal-glial interactions and connectivity in the central nervous system was developed. BMPS from healthy donors or patients evolve from a period of differentiation to maturity over about 8 weeks, including synaptogenesis, neuron-neuron interactions (e.g. spontaneous electric field potentials) and neuronal-glial interactions (e.g. myelination of axons), which mimic the microenvironment of the central nervous system. Effects of substances on neurodevelopment may be studied during this phase of BMPS development. In an exemplary embodiment, the techniques herein were used to study Parkinson&#39;s disease (PD) by evaluating neurotoxicants with a link to PD pathogenesis. Exposure to 5 μM rotenone or 100 μM 1-methyl-4-phenylpyridinium (MPP+) (or 1 mM 1-methyl-4-phenylpyridinium (MPP+) for gene expression studies) disrupted dopaminergic neurons, as observed by immunohistochemistry and altered expression of PD-related genes (TH, TBR1, SNCA, KEAP1, NDUFB1, ATP5C1, ATP50 and CASP1), thus recapitulating hallmarks of PD pathogenesis linked to toxicant compounds in the respective animal models. The BMPS, as described herein, provide a suitable and reliable model to investigate neuron-neuroglia function in neurotoxicity or other pathogenic mechanisms. 
     There is growing concern about the continuing increase in neurodevelopmental and -degenerative disorders such as autism [1, 2], Parkinson&#39;s [3] and Alzheimer disease [4]. Although genetic factors play an important role, environmental factors such as pesticides, air pollution, cigarette smoke, and dietary toxicants appear to contribute [5, 6, 7]. Due to a lack of mechanistic understanding, it is difficult to study their contributions and interactions with respect to neurotoxicity and neurological disorders. The complexity of the CNS makes it challenging to find appropriate in vitro human-relevant models, ideally from different genetic backgrounds, that are able to recapitulate the relevant pathophysiology. The poor predictive ability of animal-based models for human health, which may fail to mimic human pathology as outlined in the costly and time-consuming current developmental neurotoxicity (DNT) guidelines, contributes to the lack of reliable information on DNT mechanisms [8]. At the same time, more than 90% of all drugs fail clinical trials after extensive animal testing [9] due, in part, to the fact that animal studies often do not reflect human physiology and inter-individual differences. Simple in vitro systems do not represent physiology and organ function [10], which creates a critical demand for better models in drug development, study of disease mechanisms and progression, bioengineering and toxicological testing. 
     Attempts to generate more complex organotypic cultures or microphysiological systems (MPS) [11, 12, 13, 14] have resulted in more physiological multicellular 3D co-culture models able to simulate a functional part of the brain [15, 16]. 3D MPS have shown increased cell survival, differentiation, cell-cell interactions and can reproduce the complexity of the organ more closely [18]. Recent US research programs by NIH, FDA, DARPA, and DTRA have initiated the systematic development of MPS, including the model presented here, and their combinations to human-on-a-chip technologies to assess the safety and efficacy of countermeasures to biological and chemical terrorism and warfare [19]. 
     The discovery of induced pluripotent stem cells (iPSC) and new protocols to differentiate them into various cell types have boosted the development of human in vitro models [20, 21]. iPSC from healthy or patient donors with a specific disease [22, 23, 24, 12] used in MPS promise more human-representative models, e.g. the brain organoids by Lancaster et al. and Kadoshima et al., have been able to recapitulate features of human cortical development [15, 16]. These complex systems present novel tools to study biological mechanisms in the CNS, however, they have certain limitations: 1) an elaborate and complex protocol, 2) size differences between organoids, 3) necrosis in the center of the organoid, 4) low reproducibility in cell differentiation. The human BMPS described herein overcomes these limitations. The reproducible in vitro iPSC-derived human 3D brain microphysiological system (BMPS) is comprised of differentiated and mature neurons and glial cells (astrocytes and oligodendrocytes). 
     The techniques herein provide a reproducible BMPS that contains several different cell types of the human brain, such as glutamatergic, dopaminergic and GABAergic neurons, astrocytes and oligodendrocytes. Moreover, the system has shown neural functionality as observed by spontaneous electrical activity and myelination of axons. Furthermore, the BMPS is reproducible from batch to batch and displays differences between healthy and patient donors. In addition, the obtained results demonstrate the application of such BMPS to the study of neurological disorders such as, for example, Parkinson&#39;s Disease (PD). 
     The brain MPS described herein is a versatile tool for more complex testing platforms and strategies as well as research into neurotoxicity (e.g., developmental), CNS physiology and pathology. Some stem cell-derived brain microphysiological systems have been developed in the latest years showing the capability to recapitulate some of the in vivo biological process [36, 37, 38]. These models have an enormous advantage over the classical in vitro models to study various differentiation mechanisms, developmental processes and diseases [15]. However, they are mostly based on human embryonic stem cells raising ethical concerns and not allowing the use of patient cells. Moreover, they require complicated protocols that may reduce the reproducibility of the system and make it difficult to use in other fields such as chemical and drug screening. Some of these complex organoids have a large diameter, which can lead to extensive cell death, visible in the core of these tissues [15]. This may be due to insufficient diffusion of nutrients and oxygen in these non-vascularized systems, which may generate artifacts in toxicological and disease measurements and make it difficult to study different endpoints in a medium- to high-throughput manner. In addition, it will be challenging to adapt endpoints, established for relative simple 2D cultures, to such complex models. In the study described herein, the ability to generate a high number of viable (about 800 per batch), BMPS that are homogeneous in size (e.g., about 300 μm) and shape using iPSC by applying a constant or regular gyratory shaking or stirring technique as described earlier for rat re-aggregating brain cell cultures [40] is shown. Control of the size using specific shaker speed allowed the aggregates to be maintained below 350 μM in diameter ( FIG.  1 B ) and avoid disparate morphology and/or necrosis in the middle of the organoids. Moreover, a spherical homogeneous shape facilitates fluorescent quantification and further imaging-based endpoints as well as reproducibility between aggregates. The BMPS had reproducible cell composition by immunomorphological quantification, assessment of imaging-based endpoints and neurophysiological testing. 
     The 3D differentiation protocol described herein covered stages from neuronal precursors to different cell types of the mature CNS. After 2 weeks, BMPS consisted of an immature population of cells, showing minimal neuronal networks, low percentage of mature astrocytes and oligodendrocytes, with no myelin basic protein expression ( FIG.  1 C ). Cell populations in the BMPS were further differentiated and matured over time ( FIG.  2 A ). Evidence of iPSC differentiation into mature BMPS was supported by decreased Nestin expression over time. Nestin is normally expressed in embryonic tissue and its expression decreases with age in humans, therefore its decrement is a sign of maturation towards the adult phenotype [41, 42]. Also, the increasing presence of mature neuronal and glial markers such as MAP2, GFAP, Olig1 and MBP corroborate differentiation of the system. Different markers of pluripotency and proliferation decreased during the differentiation process, indicating maturing of the in vitro system ( FIGS.  1 C and  1 D ). Neuronal precursor markers such as Nestin, SOX1, SOX2 and the proliferation marker Ki67 decreased at the gene expression level and in flow cytometry measurements during the differentiation process ( FIGS.  1 C and  1 D ). Gene expression studies, flow cytometry, image analysis, immunostaining and miRNA studies have demonstrated an increase of cell maturation markers, which follows the BMPS differentiation ( FIGS.  1 A- 1 D,  2 A- 2 H and  9 A- 9 C ). Obtained data demonstrate that this simple protocol is sufficient to generate representative CNS cell phenotypes that can reproduce various stages of differentiation. The presence of GABAergic neurons, dopaminergic neurons and glutamatergic neurons was observed by immunohistochemistry and real-time-PCR data ( FIG.  1 C  and  FIG.  2 B ). In addition, miRNAs such as mir-124, mir-132, mir-128, mir-137 and mir133b with a role in nervous system differentiation and neuronal degeneration [43, 44] increased during differentiation in patterns consistent with the in vivo situation. Moreover, the BMPS described herein produced spontaneous electrical activity ( FIG.  3   ) confirming neuronal functionality of the system. However, further optimizations of the electrophysiological measurements using MEAs in 3D systems are needed. 
     Most of the brain MPS published so far are entirely focused on neurons and not glia populations [45, 46]; the brain MPS described herein is the first 3D model with fully characterized mature human oligodendrocytes, astrocytes and neurons, derived from iPSC. Astrocytes and oligodendrocytes play an important role during neuronal development, plasticity and neuronal injury. Astrocytes have a role in protecting neurons, increasing neuronal viability and mitochondrial biogenesis from both exogenous (e.g. chemicals) or endogenous (such as glutamate-induced excitotoxicity or the Alzheimer related Aβ1-42) toxicity [47, 48, 49, 50]. Astrocytes have an especially important role in neuroprotection from oxidative stress. Oxidative stress is known to be involved in a number of neuropathological conditions (such as neurodegenerative diseases) [51, 52, 53]. Thus, the presence of astrocytes in a biological system to study disease is crucial due to their role in detoxification and neuronal protection. Immunochemistry results from the iPSC-derived BMPS showed low numbers of astrocytes (GFAP-positive cells) at 2 weeks of differentiation, which increased continuously throughout differentiation ( FIG.  2 F- 2 H , and  FIG.  2 A ). Real-time RT-PCR data supports these findings, as a continuous increase in both s100b and GFAP mRNA levels could be observed from 2 weeks up to 8 weeks old BMPS. Immunohistochemistry and RT-PCR data results showed increasing numbers of astrocytes (GFAP-positive cells) in the BMPS model, reaching 19% astrocytes of the total cell population at 8 weeks. After 4 weeks of differentiation, astrocytes demonstrated increased positive staining for GFAP and the presence of glial network was observed ( FIG.  2 C , panels g, h). At the same time, the presence of oligodendrocytes and myelination of axons could be observed in the system described herein. This process is highly important, since it is known to be involved in many degenerative diseases such as multiple sclerosis [54], congenital hypomyelination [55], progressive multifocal leukoencephalopathy caused by JC virus infection [56], periventricular leukomalacia (PVL) [57] and Alzheimer&#39;s disease [58]. Moreover, several chemicals such as ethanol [59], tellurium [60] and lead [(61, 62, 63, 64, 65] have shown to have an effect on the myelination process. 
     The presence of astroglia and oligodendroglia in the model described herein brings the system closer to the in vivo brain physiology, which is a crucial component to study neurodegeneration and neurotoxicity. In addition, the system has shown functionality as seen by imaging of cell-cell junctions, myelination, a rich astroglial network and electrical activity ( FIG.  3   ). These characteristics make the BMPS described herein a promising tool to study interactions between human neuronal cells in neurological diseases. The use of iPSCs makes it possible to study genetic factors and gene/environment interactions. 
     An assessment of the myelination process by quantification of MBP immunostaining along axons showed an increase over time reaching 42% of myelinated axons at 8 weeks ( FIG.  2 D ). 3D reconstruction of confocal z-stacks images ( FIGS.  2 C and  2 E ) and electron microscopy confirmed the wrapping of axonal structures after 8 weeks of differentiation ( FIG.  2 C ). These findings are of particular relevance since myelin is a critical element for proper neuronal function and development, the ensheathment of axons by myelin allows faster action potential transmission, reduces axonal energy consumption and protects the axons from degeneration[79]. Furthermore, recent evidence suggests that oligodendrocytes and myelin have a role in the metabolic support of axons independent of their role in action potential conduction, highlighting their importance in neuronal survival[80]. The ability of assessing oligodendroglia function and mechanisms associated with myelination in the BMPS model provide an excellent tool for future studies of neurological disorders such as multiple sclerosis and other demyelinating disorders. 
     In one embodiment, the model described herein is useful for studying Parkinson&#39;s disease (PD). Traditionally, PD has been described as a pre-synaptic degenerative process that affects dopaminergic neurons and induces a fundamental motor disorder [66], however, non-motor symptoms can also be present [67]. Research in Parkinson&#39;s disease is experiencing an upswing at the moment, owing to a lack of curative drugs for the large number of patients. Drug testing is nearly exclusively performed in vivo in the so-called MPTP (the parent compound to the metabolite MPP+ used here), rotenone, methamphetamine and 6-hydroxydopamine models requiring tens of thousands of animals [68, 69, 70]. These model toxins are mainly used in mice and primates (and less in cell cultures) to model a disease state resembling PD. Human neurons, which would be most relevant, are not usually available and existing cell lines are only very poor substitutes. The model described herein shows that treatment with MPP+ or rotenone induced specific degeneration of dopaminergic neurons in agreement with Parkinson patients and current animal models of the disease ( FIGS.  4 E and  4 F ). The BMPS PD model has shown to recapitulate some of the molecular mechanisms of the human disease, e.g. increase in ROS production ( FIGS.  4 B and  3 D ) and changes in genes related to PD ( FIG.  4 G ). BMPS treated with rotenone or MPP+ had decreased TH gene expression compared to controls, supporting the results presented in  FIGS.  4 E and  4 F  where the dopaminergic neuronal phenotype is altered after treatment with the two chemicals. TBR1 encodes a transcription factor involved in the regulation of developmental processes. It also plays a role in major neurological diseases such as Alzheimer Disease and PD [71]. This gene was down-regulated after treatment with non-cytotoxic concentrations of MPP+ and rotenone. At the same time, mRNA levels of SNAC were altered. α-Synucleinopathy (common in Parkinson) is a neurodegenerative disease, which consists of the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibers or glial cells [72]. Alpha-synuclein plays regulatory roles such as synaptic maintenance, mitochondrial homeostasis, proteasome function, dopamine metabolism [73]. Reduction of SNCA (the alpha-synuclein encoding gene) after treatment with 5 μM rotenone and to a lesser extent after 1 mM MPP+ exposure could be explained by the alteration of alpha-synuclein protein metabolism. However, it may be that longer exposure times are required to produce an increase in gene expression. Caspase-1 (CASP1) expression increased significantly after 24 h exposure to 1 NM MPP+. Recently, some studies have identified human enzyme caspase-1 as the protease that cleaves α-synuclein in vivo [74]. This cleavage generates α-synuclein fragments that are prone to toxic aggregate formation. Finally, effects upon genes related with mitochondrial function (such as NDUFB1, ATP5C1 and ATP50) were down-regulated, more strongly in BMPS treated with MPP+ than rotenone. Changes in NDUFB1, indicate an alteration in mitochondrial function, agreeing with the phenomena already described in Parkinson&#39;s disease. This downregulation is linked to the increase in KEAP1 expression (oxidative stress marker) after 24 h exposure to 1 mM MPP+. The high variability in some of the genes may be explained by the selective effects of these chemicals (especially MPP+) to dopaminergic neurons, which represent only a subpopulation within the BMPS. While rotenone and MPP+ alter gene expression of this cell population, the other populations presented in BMPS appear not to be affected. Further studies using cell sorting could identify cell-specific effects. 
     This disclosure provides for a description of a brain microphysiological system aiming to study various aspects of brain development, pathophysiology and disturbance by genetic and environmental factors. The possibilities to study developmental and neurodegenerative disorders, infections, toxicity and trauma are emerging with such a system. Furthermore, the potential to use iPSC from different donors adds a personalized component to these studies. The high reproducibility and relatively easy protocol, enables future higher throughput testing of chemicals, and drugs and their potential to induce or treat diseases. 
     Autism 
     Autism is a highly variable neurodevelopmental disorder that first appears during infancy or childhood, and generally follows a steady course without remission. Patients with autism may be severely impaired in some respects but normal, or even superior, in others. Overt symptoms gradually begin after the age of six months, become established by age two or three years, and tend to continue through adulthood, although often in more muted form. It is distinguished not by a single symptom, but by a characteristic triad of symptoms: impairments in social interaction; impairments in communication; and restricted interests and repetitive behavior. Other aspects, such as atypical eating, are also common but are not essential for diagnosis. Autism&#39;s individual symptoms occur in the general population and appear not to associate highly, without a sharp line separating pathologically severe from common traits. 
     While autism is highly heritable, researchers suspect both environmental and genetic factors as causes. In rare cases, autism is strongly associated with agents that cause birth defects. Controversies surround other proposed environmental causes; for example, the vaccine hypotheses have been disproven. Autism affects information processing in the brain by altering how nerve cells and their synapses connect and organize; how this occurs is not well understood. It is one of three recognized disorders in the autism spectrum (ASDs), the other two being Asperger syndrome, which lacks delays in cognitive development and language, and pervasive developmental disorder, not otherwise specified (commonly abbreviated as PDD-NOS), which is diagnosed when the full set of criteria for autism or Asperger syndrome are not met. 
     Globally, autism is estimated to affect 21.7 million people as of 2013. As of 2010, the number of people affected is estimated at about 1-2 per 1,000 worldwide. It occurs four to five times more often in boys than girls. About 1.5% of children in the United States (one in 68) are diagnosed with ASD as of 2014, a 30% increase from one in 88 in 2012. The rate of autism among adults aged 18 years and over in the United Kingdom is 1.1%. The number of people diagnosed has been increasing dramatically since the 1980s, partly due to changes in diagnostic practice and government-subsidized financial incentives for named diagnoses; the question of whether actual rates have increased is unresolved. 
     Autism has a strong genetic basis, although the genetics of autism are complex and it is unclear whether ASD is explained more by rare mutations with major effects, or by rare multigene interactions of common genetic variants. Complexity arises due to interactions among multiple genes, the environment, and epigenetic factors which do not change DNA but are heritable and influence gene expression. Studies of twins suggest that heritability is 0.7 for autism and as high as 0.9 for ASD, and siblings of those with autism are about 25 times more likely to be autistic than the general population. However, most of the mutations that increase autism risk have not been identified. Typically, autism cannot be traced to a Mendelian (single-gene) mutation or to a single chromosome abnormality, and none of the genetic syndromes associated with ASDs have been shown to selectively cause ASD. Numerous candidate genes have been located, with only small effects attributable to any particular gene. The large number of autistic individuals with unaffected family members may result from copy number variations-spontaneous deletions or duplications in genetic material during meiosis. Hence, a substantial fraction of autism cases may be traceable to genetic causes that are highly heritable but not inherited: that is, the mutation that causes the autism is not present in the parental genome. 
     Several lines of evidence point to synaptic dysfunction as a cause of autism. Some rare mutations may lead to autism by disrupting some synaptic pathways, such as those involved with cell adhesion. Gene replacement studies in mice suggest that autistic symptoms are closely related to later developmental steps that depend on activity in synapses and on activity-dependent changes. All known teratogens (agents that cause birth defects) related to the risk of autism appear to act during the first eight weeks from conception, and though this does not exclude the possibility that autism can be initiated or affected later, there is strong evidence that autism arises very early in development. 
     Exposure to air pollution during pregnancy, especially heavy metals and particulates, may increase the risk of autism. Environmental factors that have been claimed to contribute to or exacerbate autism, or may be important in future research, include certain foods, infectious diseases, solvents, diesel exhaust, PCBs, phthalates and phenols used in plastic products, pesticides, brominated flame retardants, alcohol, smoking, illicit drugs, vaccines, and prenatal stress, although no links have been found, and some have been completely disproven. 
     Autism does not have a clear unifying mechanism at either the molecular, cellular, or systems level; it is not known whether autism is a few disorders caused by mutations converging on a few common molecular pathways, or is (like intellectual disability) a large set of disorders with diverse mechanisms. Autism appears to result from developmental factors that affect many or all functional brain systems, and to disturb the timing of brain development more than the final product. Neuroanatomical studies and the associations with teratogens strongly suggest that autism&#39;s mechanism includes alteration of brain development soon after conception. This anomaly appears to start a cascade of pathological events in the brain that are significantly influenced by environmental factors. Just after birth, the brains of children with autism tend to grow faster than usual, followed by normal or relatively slower growth in childhood. It is not known whether early overgrowth occurs in all children with autism. It seems to be most prominent in brain areas underlying the development of higher cognitive specialization. Hypotheses for the cellular and molecular bases of pathological early overgrowth include the following: an excess of neurons that causes local over connectivity in key brain regions, disturbed neuronal migration during early gestation, unbalanced excitatory-inhibitory networks, and abnormal formation of synapses and dendritic spines, for example, by modulation of the neurexin-neuroligin cell-adhesion system, or by poorly regulated synthesis of synaptic proteins. 
     The immune system is thought to play an important role in autism. Children with autism have been found by researchers to have inflammation of both the peripheral and central immune systems as indicated by increased levels of pro-inflammatory cytokines and significant activation of microglia. Biomarkers of abnormal immune function have also been associated with increased impairments in behaviors that are characteristic of the core features of autism such as deficits in social interactions and communication. Interactions between the immune system and the nervous system begin early during the embryonic stage of life, and successful neurodevelopment depends on a balanced immune response. It is thought that activation of a pregnant mother&#39;s immune system such as from environmental toxicants or infection can contribute to causing autism through causing a disruption of brain development. This is supported by recent studies that have found that infection during pregnancy is associated with an increased risk of autism. 
     The relationship of neurochemicals to autism is not well understood; several have been investigated, with the most evidence for the role of serotonin and of genetic differences in its transport. The role of group I metabotropic glutamate receptors (mGluR) in the pathogenesis of fragile X syndrome, the most common identified genetic cause of autism, has led to interest in the possible implications for future autism research into this pathway. Some data suggests neuronal overgrowth potentially related to an increase in several growth hormones or to impaired regulation of growth factor receptors. Also, some inborn errors of metabolism are associated with autism, but probably account for less than 5% of cases. 
     The mirror neuron system (MNS) theory of autism hypothesizes that distortion in the development of the MNS interferes with imitation and leads to autism&#39;s core features of social impairment and communication difficulties. The MNS operates when an animal performs an action or observes another animal perform the same action. The MNS may contribute to an individual&#39;s understanding of other people by enabling the modeling of their behavior via embodied simulation of their actions, intentions, and emotions. Several studies have tested this hypothesis by demonstrating structural abnormalities in MNS regions of individuals with ASD, delay in the activation in the core circuit for imitation in individuals with Asperger syndrome, and a correlation between reduced MNS activity and severity of the syndrome in children with ASD. However, individuals with autism also have abnormal brain activation in many circuits outside the MNS and the MNS theory does not explain the normal performance of children with autism on imitation tasks that involve a goal or object. 
     The under connectivity theory of autism hypothesizes that autism is marked by under functioning high-level neural connections and synchronization, along with an excess of low-level processes. Evidence for this theory has been found in functional neuroimaging studies on autistic individuals and by a brainwave study that suggested that adults with ASD have local over connectivity in the cortex and weak functional connections between the frontal lobe and the rest of the cortex. Other evidence suggests the under connectivity is mainly within each hemisphere of the cortex and that autism is a disorder of the association cortex. 
     From studies based on event-related potentials, transient changes to the brain&#39;s electrical activity in response to stimuli, there is considerable evidence for differences in autistic individuals with respect to attention, orientation to auditory and visual stimuli, novelty detection, language and face processing, and information storage; several studies have found a preference for nonsocial stimuli. For example, magnetoencephalography studies have found evidence in children with autism of delayed responses in the brain&#39;s processing of auditory signals. 
     Relations have been found between autism and schizophrenia based on duplications and deletions of chromosomes; research showed that schizophrenia and autism are significantly more common in combination with 1q21.1 deletion syndrome. Research on autism/schizophrenia relations for chromosome 15 (15q13.3), chromosome 16 (16p13.1) and chromosome 17 (17p12) are inconclusive. 
     Diagnosis is based on behavior, not cause or mechanism. Under the DSM-5, autism is characterized by persistent deficits in social communication and interaction across multiple contexts, as well as restricted, repetitive patterns of behavior, interests, or activities. These deficits are present in early childhood, typically before age three, and lead to clinically significant functional impairment. Sample symptoms include lack of social or emotional reciprocity, stereotyped and repetitive use of language or idiosyncratic language, and persistent preoccupation with unusual objects. The disturbance must not be better accounted for by Rett syndrome, intellectual disability or global developmental delay. ICD-10 uses essentially the same definition. A pediatrician commonly performs a preliminary investigation by taking developmental history and physically examining the child. If warranted, diagnosis and evaluations are conducted with help from ASD specialists, observing and assessing cognitive, communication, family, and other factors using standardized tools, and taking into account any associated medical conditions. A pediatric neuropsychologist is often asked to assess behavior and cognitive skills, both to aid diagnosis and to help recommend educational interventions. 
     Clinical genetics evaluations are often done once ASD is diagnosed, particularly when other symptoms already suggest a genetic cause. Although genetic technology allows clinical geneticists to link an estimated 40% of cases to genetic causes, consensus guidelines in the US and UK are limited to high-resolution chromosome and fragile X testing. Metabolic and neuroimaging tests are sometimes helpful, but are not routine. 
     Many medications are used to treat ASD symptoms that interfere with integrating a child into home or school when behavioral treatment fails. More than half of US children diagnosed with ASD are prescribed psychoactive drugs or anticonvulsants, with the most common drug classes being antidepressants, stimulants, and antipsychotics. Antipsychotics, such as risperidone and aripiprazole, have been found to be useful for treating some conditions associated with autism, including irritability, repetitive behavior, and sleeplessness. A person with ASD may respond atypically to medications, the medications can have adverse effects, and no known medication relieves autism&#39;s core symptoms of social and communication impairments. Experiments in mice have reversed or reduced some symptoms related to autism by replacing or modulating gene function, suggesting the possibility of targeting therapies to specific rare mutations known to cause autism. Although many alternative therapies and interventions are available, few are supported by scientific studies. Some alternative treatments may place the child at risk. A 2008 study found that compared to their peers, autistic boys have significantly thinner bones if on casein-free diets; in 2005, botched chelation therapy killed a five-year-old child with autism. There has been early research looking at hyperbaric treatments in children with autism. 
     Parkinson&#39;s Disease 
     Parkinson&#39;s disease (PD, also known as idiopathic or primary parkinsonism, hypokinetic rigid syndrome (HRS), or paralysis agitans) is a degenerative disorder of the central nervous system mainly affecting the motor system. The motor symptoms of Parkinson&#39;s disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain. The causes of this cell death are poorly understood. Early in the course of the disease, the most obvious symptoms are movement-related; these include shaking, rigidity, slowness of movement and difficulty with walking and gait. Later, thinking and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease, and depression is the most common psychiatric symptom. Other symptoms include sensory, sleep and emotional problems. Parkinson&#39;s disease is more common in older people, with most cases occurring after the age of 50; when it is seen in young adults, it is called young onset PD (YOPD). 
     The main motor symptoms are collectively called “parkinsonism,” or a “parkinsonian syndrome.” The disease can be either primary or secondary. Primary Parkinson&#39;s disease is referred to as idiopathic (having no known cause), although some atypical cases have a genetic origin, while secondary parkinsonism is due to known causes like toxins. The pathology of the disease is characterized by the accumulation of a protein into Lewy bodies in neurons, and insufficient formation and activity of dopamine in certain parts of the midbrain. Where the Lewy bodies are located is often related to the expression and degree of the symptoms of an individual. Diagnosis of typical cases is mainly based on symptoms, with tests such as neuroimaging being used for confirmation. 
     Diagnosis of Parkinson&#39;s disease involves a physician taking a medical history and performing a neurological examination. There is no lab test that will clearly identify the disease, but brain scans are sometimes used to rule out disorders that could give rise to similar symptoms. People may be given levodopa and resulting relief of motor impairment tends to confirm diagnosis. The finding of Lewy bodies in the midbrain on autopsy is usually considered proof that the person had Parkinson&#39;s disease. The progress of the illness over time may reveal it is not Parkinson&#39;s disease, and some authorities recommend that the diagnosis be periodically reviewed. Other causes that can secondarily produce a parkinsonian syndrome are Alzheimer&#39;s disease, multiple cerebral infarction and drug-induced parkinsonism. Parkinson plus syndromes such as progressive supranuclear palsy and multiple system atrophy must be ruled out. Anti-Parkinson&#39;s medications are typically less effective at controlling symptoms in Parkinson plus syndromes. Faster progression rates, early cognitive dysfunction or postural instability, minimal tremor or symmetry at onset may indicate a Parkinson plus disease rather than PD itself. Genetic forms are usually classified as PD, although the terms familial Parkinson&#39;s disease and familial parkinsonism are used for disease entities with an autosomal dominant or recessive pattern of inheritance. 
     The PD Society Brain Bank criteria require slowness of movement (bradykinesia) plus either rigidity, resting tremor, or postural instability. Other possible causes for these symptoms need to be ruled out prior to diagnosis with PD. Finally, three or more of the following features are required during onset or evolution: unilateral onset, tremor at rest, progression in time, asymmetry of motor symptoms, response to levodopa for at least five years, clinical course of at least ten years and appearance of dyskinesias induced by the intake of excessive levodopa. Accuracy of diagnostic criteria evaluated at autopsy is 75-90%, with specialists such as neurologists having the highest rates. Computed tomography (CT) and conventional magnetic resonance imaging (MRI) brain scans of people with PD usually appear normal. These techniques are nevertheless useful to rule out other diseases that can be secondary causes of parkinsonism, such as basal ganglia tumors, vascular pathology and hydrocephalus. A specific technique of MRI, diffusion MRI, has been reported to be useful at discriminating between typical and atypical parkinsonism, although its exact diagnostic value is still under investigation. Dopaminergic function in the basal ganglia can be measured with different PET and SPECT radiotracers. Examples are ioflupane (123I) (trade name DaTSCAN) and iometopane (Dopascan) for SPECT or fluorodeoxyglucose (18F) and DTBZ for PET. A pattern of reduced dopaminergic activity in the basal ganglia can aid in diagnosing PD. 
     Treatments, typically the medications L-DOPA and dopamine agonists, improve the early symptoms of the disease. As the disease progresses and dopaminergic neurons continue to be lost, these drugs eventually become ineffective at treating the symptoms and at the same time produce a complication marked by involuntary writhing movements. Surgery and deep brain stimulation have been used to reduce motor symptoms as a last resort in severe cases where drugs are ineffective. Although dopamine replacement alleviates the symptomatic motor dysfunction, its effectiveness is reduced as the disease progresses, leading to unacceptable side effects such as severe motor fluctuations and dyskinesias. Furthermore, there is no therapy that will halt the progress of the disease. Moreover, this palliative therapeutic approach does not address the underlying mechanisms of the disease. 
     The term parkinsonism is used for a motor syndrome whose main symptoms are tremor at rest, stiffness, slowing of movement and postural instability. Parkinsonian syndromes can be divided into four subtypes according to their origin: primary or idiopathic, secondary or acquired, hereditary parkinsonism, and Parkinson plus syndromes or multiple system degeneration. Usually classified as a movement disorder, PD also gives rise to several non-motor types of symptoms such as sensory deficits, cognitive difficulties or sleep problems. Parkinson plus diseases are primary parkinsonisms which present additional features. They include multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and dementia with Lewy bodies. 
     In terms of pathophysiology, PD is considered a synucleiopathy due to an abnormal accumulation of alpha-synuclein protein in the brain in the form of Lewy bodies, as opposed to other diseases such as Alzheimer&#39;s disease where the brain accumulates tau protein in the form of neurofibrillary tangles. Nevertheless, there is clinical and pathological overlap between tauopathies and synucleinopathies. The most typical symptom of Alzheimer&#39;s disease, dementia, occurs in advanced stages of PD, while it is common to find neurofibrillary tangles in brains affected by PD. Dementia with Lewy bodies (DLB) is another synucleinopathy that has similarities with PD, and especially with the subset of PD cases with dementia. However, the relationship between PD and DLB is complex and still has to be clarified. They may represent parts of a continuum or they may be separate diseases. 
     Mutations in specific genes have been conclusively shown to cause PD. These genes encode alpha-synuclein (SNCA), parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2 or dardarin), PTEN-induced putative kinase 1 (PINK1), DJ-1 and ATP13A2. In most cases, people with these mutations will develop PD. With the exception of LRRK2, however, they account for only a small minority of cases of PD. The most extensively studied PD-related genes are SNCA and LRRK2. Mutations in genes including SNCA, LRRK2 and glucocerebrosidase (GBA) have been found to be risk factors for sporadic PD. Mutations in GBA are known to cause Gaucher&#39;s disease. Genome-wide association studies, which search for mutated alleles with low penetrance in sporadic cases, have now yielded many positive results. 
     The role of the SNCA gene is important in PD because the alpha-synuclein protein is the main component of Lewy bodies. The histopathology (microscopic anatomy) of the substantia nigra and several other brain regions shows neuronal loss and Lewy bodies in many of the remaining nerve cells. Neuronal loss is accompanied by death of astrocytes (star-shaped glial cells) and activation of the microglia (another type of glial cell). Lewy bodies are a key pathological feature of PD. 
     Alzheimer&#39;s Disease 
     Alzheimer&#39;s disease (AD) accounts for 60% to 70% of cases of dementia. It is a chronic neurodegenerative disease that often starts slowly, but progressively worsens over time. The most common early symptom is short-term memory loss. As the disease advances, symptoms include problems with language, mood swings, loss of motivation, disorientation, behavioral issues, and poorly managed self-care. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the average life expectancy following diagnosis is three to nine years. The cause of Alzheimer&#39;s disease is poorly understood. About 70% of the risk is believed to be genetic with many genes involved. Other risk factors include a history of head injuries, hypertension, or depression. The disease process is associated with plaques and tangles in the brain. 
     Alzheimer&#39;s disease is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus. Alzheimer&#39;s disease has been hypothesized to be a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, 39-43 amino acids in length, called beta-amyloid (also written as A-beta or Aβ). Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron&#39;s membrane. APP is critical to neuron growth, survival and post-injury repair. In Alzheimer&#39;s disease, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis. One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques. 
     A probable diagnosis is based on the history of the illness and cognitive testing with medical imaging and blood tests to rule out other possible causes. Initial symptoms are often mistaken for normal ageing. Examination of brain tissue is needed for a definite diagnosis. Alzheimer&#39;s disease is diagnosed through a complete medical assessment. There is no one clinical test that can determine whether a person has Alzheimer&#39;s. Usually several tests are performed to rule out any other cause of dementia. The only definitive method of diagnosis is examination of brain tissue obtained from a biopsy or autopsy. Tests (such as blood tests and brain imaging) are used to rule out other causes of dementia-like symptoms. Laboratory tests and screening include: complete blood cell count; electrolyte panel; screening metabolic panel; thyroid gland function tests; vitamin B-12 folate levels; tests for syphilis and, depending on history, for human immunodeficiency antibodies; urinalysis; electrocardiogram (ECG); chest X-ray; computerized tomography (CT) head scan; and an electroencephalogram (EEG). A lumbar puncture may also be informative in the overall diagnosis. 
     There are no known medications or supplements that decrease risk of Alzheimer&#39;s. Additionally, no known treatments stop or reverse Alzheimer&#39;s progression, although some may temporarily improve symptoms. 
     This invention is further illustrated by the following examples, which should not be construed as limiting. The contents of all references, patents, and published patent applications cited throughout this application, as well as the figures, are incorporated herein by reference. 
     EXAMPLES 
     Example 1: Characterization of BMPS by Expression of Neural Specific Genes During Differentiation 
     According to the techniques herein, the BMPS model established herein follows a stepwise differentiation protocol ( FIG.  1 A ). In the final step, cells were differentiated into various neuronal and glial cell types during constant gyratory shaking. Briefly, the BMPS were established as follows: cells were differentiated, by addition of B27, GDNF and BDNF and withdrawal of stempro, basic FGF and EGF, into different neuronal and glial cell types with CNS functions during constant gyratory shaking. Advantageously, the techniques herein provide that the BMPS that were produced were of a spherical shape and a consistent size. For example, the BMPS showed spherical shapes and controlled sizes that were below 350 μm after 17 days in culture, a size that avoids necrosis in the center of the aggregate ( FIG.  1 B ) that occurs in larger spheroids (e.g., &gt;350 μm) due to nutrient and oxygen deprivation. Nutrient and oxygen deprivation-induced necrosis could produce artifacts in the different endpoints measured, especially in disease and toxicity studies. Five days after initiation of aggregation in NPC medium, spheres were on average 130±5 μm in diameter; the size increased to 300±40 μm during the first 17 days in differentiation medium. From day 17 onwards size remained constant around 310 μm. Advantageously, this technique significantly increases throughput of BMPS production by allowing simultaneous production of several batches with different conditions. Without the shaking condition, aggregates tend to stick together, grow in different shapes, attach to the bottom and in some point get necrotic in the middle of the sphere. Thus, constant gyratory shaking technology is a suitable method to control the shape and size of BMPS. 
     In order to characterize different stages of the differentiation and maturation process, BMPS were collected every week up to 8 weeks of differentiation (FIGS.  1 C 1 -C 5 ). Analysis of different neuronal and glial cell-specific genes by real-time reverse transcription polymerase chain reaction (RT-PCR) was performed to characterize the presence of neurons, astrocytes, oligodendrocytes and neural precursor cells (NPC). NPC are self-renewing and proliferating multi-potent cells able to generate different cell types of the central nervous system. The differentiation of NPC in 3D was initiated by changing the medium to differentiation medium. Gene expression of the cell proliferation marker Ki67 decreased 95% after 2 weeks of differentiation (FIG.  1 C 1 , proliferation and stem cell markers). The remaining Ki67 expression appears to be due to the presence of a small population of NPC and other proliferating cell types such as oligodendrocytes and astrocytes (FIG.  1 C 2 , astroglia and oligodendroglia). Astrocyte-specific genes (S100B and GFAP) showed a constant increase after two weeks, while, differentiation of oligodendrocytes was induced later, after six weeks of differentiation as shown by OLIG2 gene expression (FIG.  1 C 2 ). 
     Gene expression of specific neurotransmitters or their receptors was used to characterize the identity of different neuronal populations and the differentiation patterns of the human iPSC derived BMPS (FIG.  1 C 4 , neuronal markers; right y-axis relative quantification of GRIN1 and GABRA1; MBP, FOXA2, and SLC1A3). GRIN1 encodes the essential Glutamate [NMDA] receptor subunit zeta-1 [25] was increased at very early stages of differentiation (one week after induction of differentiation) and continued to increase up to 5 weeks when it reached a plateau (FIG.  1 C 4 ). Similarly, GAD1, a GABAergic neuronal gene marker which encodes the Glutamate decarboxylase 1, and catalyzes decarboxylation of glutamate to GABA, showed an increase in expression during the first 4 weeks of differentiation, reaching a plateau thereafter (FIG.  1 C 4 ). The expression of tyrosine hydroxylase (TH) a gene, which identifies dopaminergic neurons, was observed first after three weeks, showing delayed differentiation compared to glutamatergic neurons. The expression of TH increased constantly thereafter reaching an 86-fold increase at seven weeks compared to NPC (week 0; FIG.  1 C 4 ). GABRA1, which encodes the gamma-aminobutyric acid (GABA) receptor, showed a steady increase of expression after 2 weeks and reached its maximum increase of a 150-fold change at 8 weeks compared to week 0 (FIG.  1 C 4 ). Moreover other markers for specific part of the brain, such as ventral midbrain neuron marker LMX1A, FOXO1 and FOXA2 (Hedlund et al., 2016; Stott et al., 2013), cerebral cortex marker FOXO4, or markers for myelination CNP and MBP (Li and Richardson, 2008; Agrawal et al., 1994) and L-glutamate transport SLC1A6 (Sery et al., 2015) has been studied ( FIG.  1 D  d). Based on the patterns of expression of neuronal genes, the iPSC-derived BMPS model closely represents the different neuronal populations of different cortical and subcortical areas of the human CNS, suggesting that some of the mechanisms implicated in the early stages of nervous system development are reflected. 
     To prove that BMPS can be generated from different IPCs, another healthy line (IPS IMR90) and Down syndrome line (DYP0730) were used (FIG.  1 C 5 ). Both lines were able to generate BMPS and differentiated to neurons (MAP2 marker), astrocytes (GFAP marker) and oligodendrocytes (OLIG1 marker). 
     Example 2: Characterization of BMPS by Flow Cytometry Analysis Shows Neuronal Maturation of the Human Induced Pluripotent Stem Cells Over Time 
     In order to quantify cell populations in the iPSC-derived BMPS and verify the reproducibility between experiments and batches of the cell line (C1, CRL-2097), flow cytometry was performed using CNS-specific antibodies for identification of neural markers (Table 1). Flow cytometry allowed quantifying 60% of cells with proliferation marker (Ki67) at the NPCs stage (week 0), which was reduced during differentiation down to 9% at 2 weeks, 7% at 4 weeks and 1% at 8 weeks ( FIG.  1 D ), indicating a fast reduction of proliferating cells after induction of differentiation. This confirms the gene expression data and indicates a fast reduction of proliferating cells after induction of differentiation. This result was confirmed by further analysis of NPC markers such as SOX1, SOX2 and Nestin. SOX1 and SOX2 are known to be involved in the maintenance of neural progenitor cell identity. The number of SOX1-, SOX2- and NES-positive (NPC marker) cells in the NPC population (week 0) was 46%, 68% and 60%, respectively. SOX1, SOX2 and NES expression was reduced dramatically with differentiation, showing very low positive populations at eight weeks (2%, 3% and 2%, respectively). This loss in the NPC population during differentiation was corroborated by Doublecortin (DCX), a microtubule-associated protein expressed in neuroblasts and immature neurons: the number of DCX-positive cells in NPC (week o) was around 30%, which reduced to 22% at two, 17% at four and 4% at eight weeks, respectively. On the other hand, the marker for mature neurons, Tuj1 (Neuron-specific class III beta-tubulin) presented the opposite pattern. Analysis showed low levels of Tuj1-positive cells at the NPC stage (week 0). The expression of this marker in the cell population increased to 70% after 2 weeks of differentiation and remained constant up to 8 weeks. These flow cytometry experiments indicate differentiation and maturation of the BMPS over time. 
     Quantification of the cell population in at least three independent experiments showed low variability between cultures, demonstrating the reproducibility of the system. The variation (standard deviation, SD) between experiments decreased with the cell differentiation process and was very small at the latest maturation stage (eight weeks); DCX SD 0.9%, Ki67 SD 0.2%, SOX1 SD 0.7%, SOX2 SD 1.2%, NES SD 0.7% and Tuj1 SD 9.8% ( FIG.  1 E ). These results indicate that after eight weeks of differentiation the cellular composition is similar and shows high reproducibility between different BMPS experiments. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Gene and miRNAs Taqman Assays. List of 
               
               
                 the primers used for the experiments. 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Catalog 
                   
               
               
                 Assay ID 
                 Assay Type 
                 Availability 
                 Number 
                 Assay Name 
               
               
                   
               
            
           
           
               
            
               
                 Gene Expression Taqman Primers 
               
            
           
           
               
               
               
               
               
            
               
                 Hs01060665 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 BACT 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs99999901 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 18S 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs04187831 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 NES 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs01032443 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 Ki67 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs01088112 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 PAX6 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs00909233 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 GFAP 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs00300164 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 OLIG2 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs00902901 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 S100B 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs00609557 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 GRIN1 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs00165941 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 TH 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs00971228 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 GABRA1 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs01065893 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 GAD1 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs00199577 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 SYN1 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs00232429 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 TBR1 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs01003383 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 SNCA 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs01003430 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 KEAP1 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs00929425 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 NDUFB1 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs01101219 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 ATP5C1 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs00919163 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 ATP50 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs00354836 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 CASP1 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs00263981 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 CNP 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs01054576 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 FOXO1 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs00188193 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 SLC1A3 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs00936217 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 FOXO4 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs00892663 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 LMX1A 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
               
                 Hs00232764 
                 TaqMan ® Gene 
                 Inventoried 
                 4331182 
                 FOXA2 
               
               
                   
                 Expression Assay 
                   
                   
                   
               
            
           
           
               
            
               
                 miRNA Taqman Assays 
               
            
           
           
               
               
               
               
               
            
               
                 1182 
                 TaqMan ® 
                 Inventoried 
                 4427975 
                 mmu-miR- 
               
               
                   
                 microRNA Assay 
                   
                   
                 124a 
               
               
                 2216 
                 TaqMan ® 
                 Inventoried 
                 4427975 
                 hsa-miR- 
               
               
                   
                 microRNA Assay 
                   
                   
                 128a 
               
               
                 457 
                 TaqMan ® 
                 Inventoried 
                 4427975 
                 hsa-miR- 
               
               
                   
                 microRNA Assay 
                   
                   
                 132 
               
               
                 2247 
                 TaqMan ® 
                 Inventoried 
                 4427975 
                 hsa-miR- 
               
               
                   
                 microRNA Assay 
                   
                   
                 133b 
               
               
                 1129 
                 TaqMan ® 
                 Inventoried 
                 4427975 
                 mmu-miR- 
               
               
                   
                 microRNA Assay 
                   
                   
                 137 
               
               
                 1094 
                 Control miRNA 
                 Inventoried 
                 4427975 
                 RNU44 
               
               
                   
                 Assay 
               
               
                   
               
            
           
         
       
     
     Example 3: MicroRNAs as Neuronal Differentiation Markers in Human iPSC-Derived BMPS 
     MicroRNAs (miRNA), known as posttranscriptional regulators of developmental timing, have recently been established as markers to study the differentiation process [26]. Expression of neural-specific miRNAs showed strong induction of miRNAs involved in neurogenesis (FIG.  1 C 3 , miRNA). mir-124, the most abundant brain miRNA, was strongly induced in the earlier stages of differentiation, then slightly down-regulated at eight weeks of differentiation. This finding correlates with previous studies, where mir-124 was shown to promote neuronal lineage commitment at earlier stages of neural stem cells specification by targeting anti-neuronal factors [26]. mir-128, a modulator of late neural differentiation, was strongly up-regulated after 5 weeks of differentiation. mir-137, the most induced miRNA over time in the system described herein, is known as a regulator of neural differentiation of embryonic stem cells (ESCs) [27]. mir-132 and mir-133b which are involved in regulation of dopaminergic neuron maturation and function, were induced in week three of differentiation, a finding which correlates with the expression pattern of TH. Moreover, mir-132 is involved in dendritic spine formation [28]. These results support the view of a coordinated mechanism of neuronal differentiation as reflected by the patterns of neuronal gene and miRNA expression and neuronal and neurotransmitter identity. 
     Example 4: Characterization of Human BMPS by Immunohistochemistry and Electron Microscopy Shows Evidence of Differentiation into Mature Brain Cell Types 
     In order to assess the cellular composition and the process of maturation of the cells within the human BMPS, the expression of markers for different CNS cell populations including neurons and glial cells at 2, 4 and 8 weeks of differentiation were evaluated using immunohistochemistry and electron microscopy techniques. A reproducible pattern of expression consistent with maturation of the BMPS towards mature neural phenotypes was found. After 4 weeks of differentiation, the BMPS showed positive staining for mature neuronal markers such as microtubule-associated protein 2 (MAP2), neurofilament-heavy chain (NF, SMI32) and synaptophysin ( FIG.  2 A,  2 B ). Furthermore, different neuronal subtypes in the BMPS including dopaminergic (TH-positive neurons), glutamatergic (VGLUT1-positive neurons) and GABAergic interneurons (calbindin-positive neurons) ( FIG.  2 B ,  FIG.  8 A ) were observed. Moreover, the BMPS matured over time of differentiation as seen by decreased NES-positive cells ( FIG.  2 A ) and increased cell-cell interactions (neuron-neuron and neuron glia) as subsets of neurons showed several processes, which resembled dendritic and axonal projections ( FIG.  8 A ). 
     A subset of neuronal cells exhibited immunoreactivity for markers such as NOGOA, O1, O2, and CNPase ( FIG.  8 B , panels a-j; FIG.  1 C 5 ), which identifies the presence of mature oligodendrocytes in the BMPS [31, 33]. Automatic image quantification showed that oligodendrocytes (CNPase, NOGOA, and Olig1) comprised 3, 9, and 11% of the total cell population, respectively, at 8 weeks of differentiation ( FIG.  8 C ; FIG.  1 C 5 ). Similar to the in vivo physiology, these cells were immunoreactive for myelin basic protein (MBP) ( FIG.  2   ), which characterizes myelinating oligodendrocytes [32]. Moreover, they had morphological features of normal human oligodendrocytes in vivo and appeared in close contact with neuronal processes ( FIG.  8   a - b   ,  FIG.  2 C,  2 D ) Similarly, populations of neuroglia such as astrocytes and oligodendrocytes were identified using specific antibody markers. A subset of neuroglial cells exhibit immunoreactivity for markers such as NOGOA, Olig1 and CNPase ( FIGS.  2 C , panels a-f and  2 C, panel i), which identify the presence of mature oligodendrocytes in the BMPS [29, 30, 31, 32]. This pattern of immunostaining suggests that oligodendrocytes within the BMPS are functional and myelinate axons. Similar to the in vivo physiology, these cells were also immunoreactive for myelin basic protein (MBP) ( FIGS.  2 C  panel i and  2 C panel j), which characterizes myelinating oligodendrocytes [33, 30]. These cells had morphological features of normal human oligodendrocytes and appeared in close contact with neuron processes, which resemble axonal structures ( FIG.  2 C , panels j-m). In addition, a high number of mature astrocytes ( FIGS.  2 Ca,  2 Cb,  2 Cg,  2 Ch and  2 F ) at 4 and 8 weeks of differentiation were observed. Morphometric studies of neuronal processes identified by immunostaining with NF antibodies and MBP markers were used to estimate the percentage of myelinated axons within the BMPS with an average of 4% at 2 weeks, 25% at 4 weeks and 42% at 8 weeks of differentiation (p&lt;0.001) ( FIG.  2 D ). All analyzed BMPS showed similar extent of myelination at the same differentiation window. Percentages were calculated as the mean of at least 18 microscopy fields from at least 3 individual BMPS in 2 different experiments. Ultrastructural analysis by electron microscopy demonstrated cell projections, which enwrapped cell processes resembling axons after 8 weeks of differentiation ( FIG.  2 C ). 
     GFAP-positive cells formed numerous cell processes organized in a network typical for human astrocyte glial processes in vivo, which established contacts with other glial cells and neurons ( FIG.  2 Cg,  2 Ch,  2 F , and  FIG.  8 B ). Image quantification revealed 19% of astrocytes in the total population ( FIG.  8 C ). Altogether, the patterns of cell morphology, immunostaining and cell-cell interactions shown by neuronal and glial cell populations demonstrates that the BMPS recapitulates the cellular types and pattern of interactions seen in the human CNS and is, therefore, considered organotypic. 
     The morphology of cell nuclei observed by immunocytochemistry and electron microscopy showed some variation in nuclear morphology attributed to (i) cell proliferation as seen by positive staining for Ki67 and Nestin markers, and (ii) nuclear fragmentation likely associated with apoptosis as indicated by caspase 3 staining ( FIG.  2 G,  2 H ) was observed. These observations were also confirmed by electron microscopy studies at 4 and 8 weeks of differentiation ( FIG.  2 H ). The variation of nuclei morphology likely reflects the active stages of cell differentiation that BMPS exhibited during all stages of development. The presence of apoptotic nuclei likely resemble stages of cell death seen in normal neurodevelopment [34, 35]. Importantly, Caspase 3-positive nuclei did not concentrate in the center of the spheres and BMPS did not present necrosis in the center of the 3D structures ( FIG.  2 G ). Thus, Caspase3-positive nuclei do not appear linked to deprivation of oxygen or nutrients. Caspase has been quantified at eight weeks in BMPS ( FIG.  8 C ). Additionally,  FIGS.  8 D and  8 E  depict co-expression of mature oligodendroglia markers (MBP and 02) and expression of neuronal markers (VGLUT, TUJ1, SYN), respectively. 
     Further analysis of neuronal cell populations and morphology presented a pattern of evolution that suggests BMPS maturation as seen by Nestin-positive cells decreasing over time of differentiation while MBP expressing cells increased ( FIG.  2 A ). There was also evidence of cell-cell interactions as subsets of neurons showed several processes, which resemble dendritic and axonal projections that interact with other neurons as well as glial cells ( FIG.  2 B ,  FIG.  2 H ). Furthermore, cells immunostained with myelin binding protein (MBP) antibodies issued projections, which appear to enwrap neuronal processes, which resemble axons ( FIGS.  2 C , panels i-k,  2 C, panel m). The pattern of immunostaining with MBP and its association with neuronal processes suggests that oligodendrocytes within the BMPS exhibit myelinating properties such as in the human CNS in vivo. Ultrastructural analysis by electron microscopy demonstrated cell projections, which enwrapped cell processes resembling axons ( FIG.  2 C , panel m). 
     Example 5: Microelectrode Array Recording of Spontaneous Electrical Activity of BMPS 
     To test the neurophysiological properties of the cells within the BMPS model, spontaneous electrical activity in BMPS was analyzed by micro-electrode array (MEA)(see  FIG.  3    generally). BMPS were plated in 12-well or 48-well MEA plates at 8 weeks of differentiation. The aggregates were attached to the MEAs using Matrigel coating. Spontaneous electrical activity was measured starting one week after plating up to two weeks. The activity was measured for 20 minutes on 7 different days. Electrodes were considered active when the recorded activity was above 0.05 spikes/sec.  FIG.  3 A  shows a representative heatmap of a 48-well MEA plate measurement from one 20 minute recording. The heatmap represents the spike amplitude (μV) with a minimum of 0 μV and maximum of 40 μV ( FIG.  3 A ). The spikes showed a common waveform between different electrodes and measurements ( FIG.  3 B ) and neurons were repeatedly firing. 25 electrodes, distributed over 19 wells, were included after the first step of data analysis. 20 to 40% of these 25 electrodes reached the threshold of 0.05 spikes/sec during each recording.  FIG.  3 F  shows the spike events of active electrodes from one representative 20 minutes recording. These data show potential for the use of MEA to measure electrical activity of the 3D BMPS. Further optimization of the protocol may increase the measurement of the neuronal activity on the electrodes. 
     Example 6: A Human 3D Model to Study Parkinson&#39;s Disease 
     Due to the presence of TH-positive dopaminergic neurons in the iPSC-derived BMPS ( FIG.  2 B , panels k, l, and  FIG.  8   ), the possibility of using this model to study Parkinson&#39;s Disease (PD), a neurodegenerative disorder known to specifically affect dopaminergic neurons, was further explored. Two well-known neurotoxicants, which induce pathogenic processes resembling the mechanism associated with neurodegeneration in PD: the illicit drug MPTP&#39;s toxic metabolite MPP+ and the broadly used pesticide rotenone, were selected. Both MPP+ and rotenone interfere with oxidative phosphorylation in mitochondria by inhibiting complex I [36]. Initially, cytotoxicity experiments were performed to estimate sub-cytotoxic concentrations of these two compounds affecting only dopaminergic neurons ( FIGS.  4 A and  4 C ). Selective disruption of dopaminergic neurons but not of any other cell types in the systems described herein were observed with immunohistochemistry after exposure to 1p M rotenone and 100 μM MPP+ for 24 h ( FIGS.  4 E and  4 F ). This effect was likely selective even at cytotoxic concentrations of 10 μM rotenone and 1000 μM MPP+ as these concentrations did not show any alterations in other neurofilament 200-positive neurons. Lower concentrations of these compounds may induce effects in dopaminergic neurons, however, the effect was not as obvious by immunocytochemistry. Higher concentrations of rotenone and MPP+ (up to 50 μM and 5000 μM, respectively) led to general cytotoxicity and affected also other neuronal types stained positive for neurofilament 200 ( FIGS.  4 E  and F). 5 μM of rotenone and 1000 μM of MPP+ were selected for further studies as these concentrations induced clear and selective dopaminergic effects. Reactive oxygen species (ROS) were measured in the cellular medium using the OxiSelect™ In Vitro ROS/RNS Assay Kit (Cellbiolabs, San Diego, Calif.) as an indication of oxidative stress. Exposure to rotenone at 5 μM and MPP+ at 1000 μM showed an increase in ROS production after 24 hours exposure, while 12 hours showed no statistically significant changes. Real time RT-PCR was performed in order to determine effects of both chemicals on genes related to PD, mitochondrial dysfunction and oxidative stress. Tyrosine hydroxylase (TH, Dopaminergic neuronal marker) mRNA expression decreased by 84%±11 after exposure to 5 μM rotenone and 70%±9 after exposure to 1000 E M MPP+ for 24 hours. Additional genes related to PD also showed changes at sub-cytotoxic concentrations of MPP+ and rotenone. The expression of genes that encode T-box brain 1 (TBR1) and Alpha-synuclein (SNCA) protein decreased after 24 hours exposure. The reduction of TBR1 was 70±13% (rotenone) and 76±22% (MPP+) and the reduction of SNCA was 72±6% (rotenone) and 41±40% (MPP, however, BMPS exposed to 1 mM MPP+ led to no statistically significant changes in SNCA expression). Expression of genes related to mitochondrial function complex I (NDUFB1) or complex 0 (ATP5C1 or ATP50) tended to decrease in expression but these changes were not statistically significant. Caspase-1 gene expression, which has been related to SNCA, increased after 24 hours exposure to MPP+. These results demonstrate the potential of BMPS for studies elucidating molecular mechanisms of PD, lending itself to PD drug and neurotoxicity screening. 
     Example 7: Addition of Microglia 
     Peripheral blood mononuclear cells (PBMCs) are isolated from fresh or commercially available cryo-preserved whole blood of pooled healthy donors by Ficoll or Percoll gradient centrifugation. Monocyte populations are obtained by negative magnet-antibody selection after Ficoll or Percoll gradient and then re-suspend in RPMI 1640. Monocytes are cultured in macrophage serum-free medium, stimulated with a cocktail of cytokines, GM-CSF and IL-34. Monocytes may also be obtained by differentiation of iPSCs, hematopoetic or other stem cells. The microglia-like cells are combined with neuronal precursor cells in shaker cultures to preferably arrive at a final concentration of 5-8% microglia. 
     Primary monocytes or iPSC-derived monocytes may be incorporated into the system, both at early and later stages of BMPS differentiation. For the early stages, a number of 2×10 6  NPCs mixed with 2×10 4  monocytes are plated per 1 well (6 well-plate). Gyratory shaking is used at 88 rpms to generate spheres. After 2 days media are replaced with ½ CNS differentiation medial (Neurobasal® electro Medium (Gibco) supplemented with 5% B-27® Electrophysiology (Gibco), 1% glutamax (Gibco), 10 μg human recombinant GDNF (Gemini), 10 μg human recombinant BDNF (Gemini)) and ½ macrophage differentiation media (Dulbecco&#39;s modified Eagle&#39;s medium (Invitrogen) supplemented with 10% FCS, 0.055 mM β-mercaptoethanol, M-CSF (50 ng/ml), and IL-3 (25 ng/ml) (R&amp;D Systems). The medium is replaced every 3 days. 
     Monocytes can also be incorporated after BMPS differentiation. For that, BMPS are differentiated up to 8 weeks. BMPS spheres are separated in 500 μl Eppendorf tubes. 2×10 4  monocytes are added to the Eppendorf with the BMPS. Tubes are shaking manually every hour, up to 8 hours. After that, BMPS-monocytes are collected and plated in 6 well plates. Cells are kept on constant shaking until use. 
     The characterization of the immune-competent human organoids can be carried out by immunocytochemically assessing the presence of markers such as HLA-DR, and the ionized calcium-binding adapter molecule 1 (Iba1), specific microglial markers. Measures of cytokines and chemokines release and expression of receptors associated with microglia function (e.g., CCL2 and CX3CL) demonstrates successful engrafting of the microglia cells. This modified model is more suitable to investigate the neuroimmunological component associated with many substance exposures and diseases. 
     Example 8: Addition of a Blood Brain Barrier 
     The blood brain barrier (BBB) has a crucial role in neurotoxicity, being the last barrier for substances before reaching the brain. Moreover, the BBB is the bottleneck in brain drug development and is the single most important factor limiting the future growth of neurotherapeutics [81]. Most of the in vitro models do not incorporate BBB. 
     Human brain microvascular endothelial cells (hBMECs) from human iPSCs are incorporated into the BMPS by two techniques. In the first approach, mature BBB endothelial cells and neuronal precursors cells (NPCs) are combined in a single cells suspension in a ratio of 1:5, gyratory shaking or stirring are used to generated spheroids and aggregates are cultured up to 8 weeks. In the second technique, mature BMPS (8 weeks of differentiation) are covered by BBB endothelial cells using gravity systems (aggrewell, gravity well or hanging drops). Cells may be covered as well with other cell types, such as fluorescent LUHMES cells ( FIG.  7   ). 
     Example 9: Addition of Reporters 
     The BMPS gives the opportunity to develop cell-based assays allowing for high-content imaging (HCI) that can be adapted to high-throughput platforms, to evaluate the effects of toxicants on key cellular processes of neural development and physiology in the culture system. 
     Example of establishing fluorescent iPSC cell line: Creation of reporter cells lines greatly assists imaging efforts by allowing us to avoid complications associated with staining 3D cultures, to image subsets of cells, and to perform functional assays. Differentiated 3D aggregates from iPSC cultures spiked with 1-2% of iPSCs ubiquitously expressing fluorescent protein allow visualizing individual cells within the aggregates aiding quantification of phenotypic parameters, including neurite outgrowth and migration. Lines expressing markers allow measurement of synapse formation (PSD95, Synapsin 1), proliferation (Ki67), glial maturation (GFAP), and calcium signaling (GCaMP). Clustered Regularly Interspaced Short Palindromic Repeats/Cas (CRISPR) were used to create the various lines. Similar in function to the well-established zinc-finger (ZFNs) and TALEN nucleases, the Cas9-CRISPR system is a new entrant into the rapidly emerging field of genome engineering and has been quickly adopted and validated across a wide array of human stem cells. Gene-editing in hiPSCs has traditionally been a technically difficult task but with these advances it is now possible to generate reporter and mutant cell lines with genetically matched controls [83, 84, 85, 86]; essential tools not only for this project but also for the future success of using human iPSC-derived cells in quantitative live-cell phenotypic assays of toxicant testing. 
     Using the CRISPR-Cas9 system, fluorescent protein (FxP) reporter cell lines were generated by generating gRNAs targeting the gene of interested. In this system as described herein, an RNA guided Cas9 endonuclease is used in conjunction with customizable small guide RNAs (gRNAs) to target and cleave any DNA template with a GN21GG sequence; the first G is for the U6 polymerase promoter while the N21GG is for the protospacer adjacent motif (PAM) sequence requirement of Cas9 [86, 87, 89]. 
     For reporter cell generation, homology-directed repair (HDR) guides the insertion of the appropriate DNA donor fragment into a target site at regions of homology between the donor fragment and the genomic DNA target. An ES line that ubiquitously expresses GFP was created by introducing CAG promoter-driven GFP into the AAVS1 safe harbor locus, and can use these constructs to transfect iPSC cells. For other reporters, constructs may be created that will direct the integration of a self-cleaving P2A peptide sequence [90] targeted fluorescent protein cassette in frame at the stop codon of the gene of interest. The P2A sequence engineered between the C-terminus of the endogenous protein and the fluorescent protein may minimize possible fusion protein functional defects. Plasmids encoding the Cas9 nuclease, the targeting gRNA, and appropriate donor DNA will be introduced by electroporation, recombinant hiPSC clones will be manually selected and screened for the desired insertion by PCR, and the genotype may be verified by sequencing. Reporter hiPSCs will be subjected to a differentiation protocol and expression of the reporter validated by examining expression patterns and through immunohistochemistry experiments where it may be determined whether the FxP expressing cells co-label with known markers. 
     Example 10: Using Cells with Specific Genetic Backgrounds 
     The use of iPSCs, as described herein, has created new opportunities to study human diseases and gene/environment interaction [20, 21]. Fibroblasts or other somatic cells from healthy and diseased individuals can be reprogrammed into iPSCs, and subsequently be differentiated into all neural cell types. Similarly, iPSC can be genetically modified before creating the BMPS. As a proof-of-principle, iPSCs were obtained from patients with Down&#39;s syndrome (FIGS.  1 C 5  and  5 A-D), Rett Syndrome and from individuals with mutations in disrupted in schizophrenia 1 (DISC1). DISC1 may have some functional overlap with TSC-iPSCs as both are involved in the mTOR cell signaling pathway. 
     The Down&#39;s syndrome model is further characterized (see  FIGS.  5 A- 5 D ). Down&#39;s syndrome iPSCs have been successfully differentiated into neural precursor cells (NPCs). Currently the cells are differentiated in 3D and characterization by gene expression and immunohistochemistry is being performed. The Down&#39;s syndrome model has been exposed to compounds that induce oxidative stress (rotenone and paraquat). The response was compared to the model from healthy donors, which were more sensitive to these compounds than the healthy model. 
     Example 11: Combining the BMPS with Other Organoids 
     In some embodiments, BMPS may be combined with other organs and/or organ model systems. Several groups have been developing organ-on-a-chip platforms for different organs by using microfluidic techniques. Those platforms are designed to mimic in-vivo fluidic flows in the organs by separating cell culture chambers and perfusion channels, and successfully demonstrate recapitulation of iPSC-based organ functions. Together with other organ models on these platforms, the BMPS can be integrated, which allow us to untwine the complex toxicology from organ interactions. Such platforms allow (1) in-situ and high-throughput production of mini-brains on chip, (2) in-vivo like fluidic flow around mini-brains with enough supply of nutrient and small molecule through diffusion, (3) a large number of parallel test of toxic materials, and (4) a real-time monitoring of electrophysiological activities from BMPS with integrated electrodes. Companies such as TissUse GmbH have designed microfluidics platform that allow culture of floating spheres like the BMPS as described herein. 
     Example 12: Cryopreservation and Other Modes of Transportability 
     In order to e.g. incorporate the BMPS into platforms or enable any use in other laboratories, transportability of the system was optimized. Preliminary studies have shown possible recovery of the neuronal 3D aggregates after cryopreservation ( FIG.  6   ). A human embryonal carcinoma stem cell line, (hNT2), and iPSC derived-aggregates were differentiated into mature neurons (8 weeks of differentiation for each cell line) and then cryopreserved with regular cryopreservation medium (95% FBS and 5% DMSO) or STEMdiff™ Neural Progenitor Freezing Medium (Stem cells technologies). After 2 days in liquid nitrogen, cells were thawed. Freezing media was removed and fresh media was added. One day later, viability was measured using the resazurin cell viability assay. hNT2 aggregates presented a 70% decrease in viability in both freezing medias while iPSC derived mini-brains showed a 20%-35% reduction in viability ( FIG.  6   ). However, viability recovery of the 3D aggregates is currently optimized using other viability and functional assays. Optimization of this protocol will vary additives (DMSO, HES, glycerol, serum etc.), the cooling temperature gradient as well as thawing protocol. 
     Human iPSC derived mini-brains are kept in culture at 37° C. In order to transport the live mini-brains, temperature must be controlled. Different methods can be used to control temperature during transport. Heating pads combined with an insulated box have been used to transport live biological material. Disposable chemical pads employ a one-time exothermic chemical reaction such as catalyzed rusting of iron, or dissolving calcium chloride. The most common reusable heat pads are based on a chemical reaction that transforms a liquid into a solid thus releasing energy. Some new heating pads (such as Deltaphase Isothermal Pad 3SET, from Braintree Scientific, Inc.) have been able to maintain 37° C. for more than 6 hours. 3D mini-brains cultured up to 8 weeks are sent in an insulated material box with heating pads. After transport, viability may be measured. 
     Example 13: Overview 
     The techniques herein provide a human BMPS model that is a versatile tool for more complex testing platforms, as well as for research into CNS physiology, mechanisms associated with (developmental) neurotoxicity, and pathogenesis of neurological disorders. Prior art stem cell-derived brain model systems developed in the past few years have shown the capability to recapitulate some of the in vivo biological processes (Juraver-Geslin and Durand, 2015; Nakano et al., 2012; Krug et al., 2014) and have an advantage over other classical in vitro models as they facilitate the study of various differentiation mechanisms, developmental processes and diseases (Lancaster et al., 2013). Unfortunately, these prior art systems require complicated protocols that reduce the reproducibility of the system and make it difficult to use in other fields such as chemical toxicity and drug screening. Additionally, these prior art models are also limited by large diameters, which lead to extensive cell death in the interior regions due to insufficient diffusion of oxygen and nutrients (Lancaster et al., 2013) and other artifacts. 
     The techniques herein overcome the limitations of the prior art by developing a human in vitro model by the gyratory shaking technique that enables reliably generation of a high number (about 500 per six-well plate) of viable BMPS that are homogeneous in size and shape. Control of size makes it possible to keep cell aggregates below 350 μM in diameter ( FIG.  1 C ) and thereby avoid disparate morphology and/or necrosis in the center of the spheres. Moreover, the BMPS showed reproducible cell composition by immunomorphological quantification, assessment of imaging-based endpoints and flow cytometry analysis. 
     As described herein, the 3D differentiation protocol for the BMPS covers stages from neuronal precursors to different cell types of the mature CNS. As discussed in detail above, at two weeks, BMPS consisted of an immature population of cells, showing minimal neuronal networks, a low percentage of mature astrocytes and oligodendrocytes, and minimal but early stages of myelin basic protein (MBP) expression. iPSC differentiation into mature BMPS was indicated by decreasing NES expression over time and a progressive expression of mature neuronal and glial markers such as MAP2, GFAP, 01 and MBP. Gene expression studies, flow cytometry, image analysis, immunostaining and miRNA studies have shown increase of cell maturation markers, which follow the BMPS differentiation. The presence of GABAergic neurons, dopaminergic neurons and glutamatergic neurons was documented by immunohistochemistry and real-time PCR data. Moreover, the BMPS showed spontaneous electrical activity, indicating neuronal functionality of the system. 
     Since astrocytes and oligodendrocytes play important roles during neuronal development, plasticity and injury, the presence of glial cell populations in the presently disclosed BMPS model provides an excellent opportunity for the evaluation of neuronal-glial interactions and the role of glia in pathogenesis and toxicity processes. Astrocytes have an important role in protecting neurons, increasing neuronal viability and mitochondrial biogenesis from both exogenous (e.g. chemicals) and endogenous toxicity (Shinozaki et al., 2014; Aguirre-Rueda et al., 2015), especially against oxidative stress (Shao et al., 1997; Schwab and McGeer, 2008). Thus, their presence in a biological system to study disease and neurotoxicity is crucial. Immunohistochemistry and RT-PCR results showed increasing numbers of astrocytes (GFAP-positive cells) in the BMPS model reaching 19% astrocytes of the total cell population at eight weeks, which is earlier than in previously described cortical spheroids, where similar proportions of GFAP-positive cells were observed first at day 181, at day 86 the number of GFAP+ cells was below 10% (Pasca et al., 2015). 
     The most novel element of this BMPS is the presence of mature human oligodendrocytes with myelination properties, which has not been achieved in the prior art. Immunocytochemical and ultrastructural studies confirmed the morphological identity of these cells ( FIG.  2 D ) as multiple markers for mature oligodendrocytes were expressed by rounded cells with branching processes and membrane sheaths that are similar to the ones found in humans in vivo. The structure and morphology was further confirmed by electron microscopy. Quantitative assessment of the myelination process of MBP immunostaining along axons showed an increase over time of differentiation reaching 42% of myelinated axons at eight weeks ( FIG.  2 D ). 3D reconstruction of confocal z-stacks images ( FIG.  2 A ) and electron microscopy confirmed the wrapping of axonal structures after eight weeks of differentiation ( FIG.  2 C ). These findings are of particular relevance since myelin is a critical element for proper neuronal function and development, and the covering of axons by myelin allows faster action potential transmission, reduces axonal energy consumption and protects the axons from degeneration (Nave, 2010). Furthermore, recent evidence suggests that oligodendrocytes and myelin have a role in the metabolic support of axons independent of their role in action potential conduction, highlighting their importance in neuronal survival (Saab et al., 2013). This is the first time that a 3D human microphysiological system, consisting of different types of neurons and glial cells, has achieved such a high percentage of myelination. The ability to assess oligodendroglia function and mechanisms associated with myelination in this BMPS model provides an excellent tool for future studies of neurological disorders such as multiple sclerosis and other demyelinating disorders. As an illustration it was recently discovered that astroglia cells could promote oligodendrogenesis via secreted molecules (Jiang et al., 2016). A human BMPS that consist of neurons, astrocytes and oligodendrocytes is essential to evaluate this mechanism further and to develop a potential therapy for demyelinating disorders. 
     In conclusion, the techniques herein provide a BMPS that replicates crucial aspects of brain physiology and functionality. The potential for studying developmental and neurodegenerative disorders, brain infections, toxicity and trauma with such a system is growing. Furthermore, the potential to use iPSCs from different donors adds a personalized component to these studies. The high reproducibility and relatively simple protocol, enables future medium-throughput (96-well format) testing of chemicals, drugs and their potential to induce or treat diseases. 
     Methods and Materials 
     Chemicals 
     Rotenone and MPP+ were supplied from Sigma-Aldrich (St. Louis, Mo.). A 10 mM rotenone stock was prepared in DMSO Hybri-Max (Sigma) while MPP+ was diluted in water to a concentration of 30 mM. 
     iPSC Generation 
     CCD1079Sk (ATCC® CRL2097™), IPS IMR90 (WiCELL) and ATCCDYP0730 Human (IPS) Cells (ATCC® ACS1003™) fibroblasts were originally purchased from ATCC. All studies followed institutional IRB protocols approved by the Johns Hopkins University School of Medicine. Human fibroblasts and mouse embryonic fibroblasts (MEFs) were cultured in Dulbecco&#39;s modified Eagle&#39;s medium (DMEM, Mediatech Inc.) supplemented with 10% fetal bovine serum (FBS, HyClone) and 2 mM L-glutamine (Invitrogen). MEFs were derived from E13.5 CF-1 mouse embryos. Human iPCS cells were generated with the EBV-based vectors as previously described [75]. iPSC from other sources were used as well. Colonies of iPSCs were manually picked after 3-6 weeks for further expansion and characterization. iPSCs (passage ≤20) were cultured on irradiated MEFs in human embryonic stem cell (hESC) medium comprising D-MEM/F12 (Invitrogen), 20% Knockout Serum Replacement (KSR, Invitrogen), 2 mM L-glutamine (Invitrogen), 100 μM MEM NEAA (Invitrogen), 100 μM β-mercaptoethanol (Invitrogen), and 10 ng/mL human basic FGF (bFGF, PeproTech). Media were changed daily and iPSC lines were passaged using collagenase (Invitrogen, 1 mg/ml in D-MEM/F12 for 1 hr at 37° C.). These iPSC lines have been previously fully characterized [75]. 
     Neuronal Progenitor Cells (NPC) Production 
     NPC generated followed the previous published protocol [75]. Briefly, iPSCs colonies were detached from the feeder layer with collagenase (1 mg/ml) treatment for 1 hr and suspended in EB medium, comprising of FGF-2-free hESC medium supplemented with Dorsomorphin (2 μM) and A-83 (2 μM), in non-treated polystyrene plates for 4 days with a daily medium change. After 4 days, EB medium was replaced by neural induction medium (hNPC medium) comprising of DMEM/F12, N2 supplement, NEAA, heparin (2 μg/ml) for 15 more days. The floating neurospheres were then dissociated to single cells in Accutase and plated in 175 mm flasks and were allowed to expand for 7 days. NPCs were expanded in poly-1-ornithine and laminin-coated 175 mm flask on StemPro® NSC SFM (Life Technologies). Half of the media was changed every day. Cultures were maintained at 37° C. in an atmosphere of 5% CO 2 . After NPC generation, iPSCs colonies were detached and NPCs were expanded in poly-1-ornithine and laminin-coated 175 mm flask in StemPro® NSC SFM (Life Technologies). Half of the media was changed every day. Cultures were maintained at 37° C. in an atmosphere of 5% CO2. 
     BMPS Differentiation 
     At 100% confluence NPCs were detached mechanically and counted. 2×10 6  cells per well were plated in 2 ml of medium in non-treated 6 well-plates. Cells were grown in NPC media for two days under constant gyratory shaking. Subsequently, medium was changed to differentiation medium (Neurobasal® electro Medium (Gibco) supplemented with 5% B-27® Electrophysiology (Gibco), 1% glutamax (Gibco), 0.02 μg/ml human recombinant GDNF (Gemini), 0.02 μg/ml human recombinant BDNF (Gemini)). Cultures were maintained at 37° C., 5% CO 2  under constant gyratory shaking for up to 8 weeks. Differentiation medium was routinely changed every 2 days. 
     Size Measurement 
     Aggregates (n=20) from 3 independent experiments were randomly selected per time point for obtaining pictures and measuring size using SPOT software 5.0. Results were expressed as mean±SD. Cells were kept two days in NPC medium, indicated as NPC med. 2d in  FIG.  1 B . 
     RNA and miRNA Extraction 
     Total RNA was extracted from aggregates every week up to 8 weeks of differentiation using Tripure (Roche, Switzerland) according to Chomczynski and Sacchi (1987) [76]. The same RNA extraction method was used to isolate RNA after toxicant treatment. RNA quantity and purity was determined using NanoDrop 2000c (Thermo Scientific). One microgram of RNA was reverse-transcribed using the M-MI V Promega Reverse Transcriptase (Promega) according to the manufacturer&#39;s recommendations. For miRNA reverse-transcription 60 ng of RNA were reverse transcribed using TaqMan microRNA Reverse transcription kit in combination with miRNA specific stem-loop primers, which are a part of TaqMAn microRNA expression assay. Upto eight stem-loop primers were multiplexed in one reaction. 
     Quantitative RT-PCR 
     The expression of genes was evaluated using specific Taqman® gene expression assays (Life Technologies). miRNA expression was analyzed using TaqMAn microRNA expression assay in combination with TaqMan miRNA Reverse Transcription kit using protocol described in [77]. Table 1 shows a summary of the genes assayed. Real time RT-PCRs were performed using a 7500 Fast Real Time system machine (Applied Biosystems). Fold changes were calculated using the 2(−ΔΔCt) method [78]. β-actin and 18s were used as a housekeeping genes for mRNA and RNU44 for miRNA. There were no statistically significant differences in expression for β-actin, 18s, and RNU44. Data were presented as mean±SD, normalized to housekeeping genes and week 0. 
     Immunocytochemistry of the BMPS 
     BMPS aggregates were collected at 2, 4 and 8 weeks. BMPS were fixed in 4% paraformaldehyde for 1 hour, washed 3 times in PBS, then incubated for 1 hour in blocking solution consisting of 5% normal goat serum (NGS) in PBS with 0.4% TritonX (Sigma). BMPS were then incubated at 4° C. for 48 hours with a combination of primary antibodies (Table 2) diluted in PBS containing 3% NGS and 0.1% TritonX. BMPS were washed in PBS 3 times after which they were incubated with the appropriate fluorophore-tagged secondary antibody for 1 hour in PBS with 3% NGS at room temperature. Double immunostaining was visualized using the proper combination of secondary antibodies (e.g., goat anti-rabbit secondary antibody conjugated with Alexa 594 and goat anti-mouse secondary antibody conjugated with Alexa 488 (Molecular Probes). Nuclei were counterstained with DRAQ5 dye (Cell Signaling; 1:5000 in 1×PBS) or NucRed Live (Molecular Probes) for 15 minutes before mounted on slides with coverslips and Prolong Gold antifade reagent (Molecular Probes); BMPS used as negative controls for immunostaining were processed omitting the primary antibody. Images were taken using a Zeiss UV-LSM 510 confocal microscope. The experiments were performed in duplicates; at least three different fields of view were analyzed for each combination of antibodies. 3D reconstruction was done using Imaris 7.6.4 software for scientific imaging. 
                     TABLE 2                  Primary Antibodies.                                 Antibody   Host   Type   Source   Dilution               NF-H   Rabbit   Polyclonal   Enzo    1:1000       GFAP   Rabbit   Polyclonal   Dako   1:500       Olig1   Mouse   Monoclonal   Millipore   1:500       CNPase   Mouse   Monoclonal   Millipore   1:500       Calbindin   Mouse   Monoclonal   SIGMA   1:500       NOGO-A   Rabbit   Polyclonal   Santa Cruz   1:500       Map2   Mouse   Monoclonal   Chemicon    1:1000       MBP/SMI99   Mouse   Monoclonal   COVANCE    1:1000       SMI-32   Mouse   Monoclonal   Stenberger    1:2000                   Monoclonals           Synaptophysin   Mouse   Monoclonal   SIGMA   1:500       VGLUT1   Rabbit   Polyclonal   Alpha Diagnostic   1:500       TH   Mouse   Monoclonal   Millipore   1:250       Nestin   Rabbit   Polyclonal   Millipore   1:200       Ki67   Rabbit   Polyclonal   abcam   1:100       Caspase3   Rabbit   Polyclonal   R&amp;D   0.2 μg/ml       OLIG1   Mouse   Monoclonal   Millipore   1:200       TUJ1   Mouse   Monoclonal   Stemcell   1:200                   technologies           S100B   Rabbit   Polyclonal   Santa Cruz   1:200                    
Automated Quantitation of Cell Types
 
     BMPS was differentiated for 8 weeks. Randomly selected pictures from three experiments were acquired by confocal imaging and then analyzed with a custom algorithm created with the Cellomics TargetActivation (Thermo Fisher Scientific, Pittsburgh, Pa.) image-analysis software package. With this algorithm, cells were identified based on DRAQ5 stained nucleus and quantified oligodendrocytes and astrocytes based on staining of CNPase, NOGO1 and GFAP. 
     Myelination Assessment and Quantification 
     To calculate the percentage of axonal myelination, a semi-automated computer platform was used, termed computer-assisted evaluation of myelin formation (CEM) [82], which uses NIH Image J built-in tools as well as a Math lab processing functions. The results were generated as pixel counts and percent values. The percent of myelinated axons was calculated by dividing the pixel count for myelin by the pixel count for axons after cell body removal and multiplying by 100. For each time point at least 18 fields from at least two independent experiments were analyzed. 
     Electron Microscopy 
     BMPS aggregates were collected at 2, 4 and 8 weeks and were fixed in 2% glutaraldehyde and 4% formaldehyde in 0.1M Sodium Cacodylate buffer (EMS, electron microscopy sciences) pH 7.4 with 3% sucrose and 3 mM CaCl 2 . Post-fixation was done with 2% osmium for 2 hours. The BMPS aggregates were then stained en bloc with 2% uranyl acetate in distilled water for 30 min and subsequently dehydrated in graded ethanol. Embed 812 (EMS) was used as the embedding media. Thin sections (70-80 nm) were cut on a Reichert Jung Ultracut E microtome and placed on formvar coated 100 mesh copper grids. The grids were stained with uranyl acetate and followed by lead citrate. All imaging was performed on a Zeiss Libra 120 electron microscope with a Veleta (Olympus) camera. 
     Treatment and Cytotoxicity Assay 
     BMPS was exposed to different concentrations of rotenone and MPP+ for 24 and 48 hours after 4 weeks of differentiation. Rotenone working solutions were prepared in differentiation medium from 10 nM or 100 μM stocks to reach final concentrations of 0.1, 1, 10, 25 and 50 μM. DMSO was used as vehicle control. MPP+ working solutions were prepared in differentiation medium from 30 mM stocks to reach final concentrations of 10, 50, 100, 500, 1,000, 5,000 and 10,000 μM. Four independent experiments in 3 replicates were performed for each experimental condition (control and toxicant exposure for the different time points). Resazurin reduction assay was performed in order to determine cell viability after rotenone and MPP+ treatment. Resazurin (7-Hydroxy-3H-phenoxazin-3-one 10-oxide) is a blue dye that is reduced into red fluorescent resorufin by redox reactions in viable cells. 100 μl Resazurin (2 mg/ml stock) were added directly to the 6 well plates (2 ml/well). Plates were incubated for 3 h at 37° C., 5% CO 2 . Subsequently, 50 μl of medium were transferred from each well in triplicates to a 96-well plate and fluorescence was measured at 530 nm/590 nm (excitation/emission) using a multi-well fluorometric reader CytoFluor series 4000 (PerSeptive Biosystems, Inc). Data were presented as mean±SD. Statistical analysis was performed using Dunnett&#39;s test. 
     Reactive Oxygen Species Measurement 
     Reactive oxygen species (ROS) were measured in cell media collected 24 hours after treatment with 5 μM rotenone or 1,000 μM MPP+ using the OxiSelect™ In Vitro ROS/RNS Assay Kit (Cell Biolabs, San Diego, Calif.). This is a fluorescence-based assay measuring the presence of total free radicals within a sample and was used according to the manufacturer&#39;s protocol. The quenched fluorogenic dye dichlorodihydrofluorescin-DiOxyQ (DCFH-DiOxyQ) which is similar to the popular 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) is first primed with a quench removal reagent. The resulted highly reactive non-fluorescent DCFH can react with present ROS species in the cell supernatant and is then oxidized to the highly fluorescent DCF (2′,7′-dichlorodihydroxyfluorescein). At every time point, 50 μl of the cell supernatant was added to a 96-well plate in triplicates and was mixed and incubated with the DCFH-DiOxyQ for 45 minutes. The fluorescence intensity was measured with a fluorescence microplate reader at 480 nm/530 nm (excitation/emission) and was proportional to the total ROS/RNS levels within the sample. 
     Flow Cytometry 
     In order to quantify percentage of NPCs, and neurons within the aggregates, flow cytometry with NPC and neuronal markers was performed. Flow cytometry was performed according to previously published protocol [77] with some optimization steps for 3D cultures. Aggregates were washed once with PBS/1 mM EDTA and trypsinized directly in the well using TrypLE Express containing 4 units/ml DNAse for 30 min at 37° C. on the shaker. Pipetting the aggregates up and down with a 1 ml syringe and a 26G3/8 needle ensured generation of single cell suspension. Cells were counted, washed once with PBS/1 mM EDTA, fixed with 2% PFA for 20 min at 4° C., washed twice with PBS/1% BSA (wash solution I, WS I) and blocked for 30 min in blocking solution (PBS/1% BSA/0.15% saponin/10% NGS). 1×10 6  cells were stained for one hour at 4° C. with fluorochrome-conjugated antibodies dissolved in blocking solution (Table 3). Unstained cells as well as cells incubated with isotype controls were used as negative controls to set the gates for measurements. Cells were washed twice with PBS/1% BSA/0.15% saponin, once with PBS/1% BSA. Flow cytometry was performed using a Becton Dickinson FACSCalibur system by measuring 10 4  gating events per measurement. Data was analyzed using FlowJo v10 software. 
                     TABLE 3                  Antibodies for flow cytometry analysis                                 Antibodies   Host   type   Source   Dilution               Alexa Fluor ®   Mouse   Monoclonal,   BD Pharmingen   1:05       647 Nestin       clone 25               Alexa Fluor ®   Mouse   Monoclonal,   BD Pharmingen   1:05       488 β-III-       clone TUJ1               Tubulin                       PerCP-Cy ™   Mouse   Monoclonal,   BD Pharmingen   1:20       5.5 Sox2       clone 030-678               PerCP-Cy ™   Mouse   Monoclonal,   BD Pharmingen   1:20       5.5 Sox1       clone N23-844               PE Doublecortin   Mouse   Monoclonal,   BD Pharmingen   1:20               clone 30               Alexa Fluor ®   Mouse   Monoclonal,   BD Pharmingen   1:20       647 Ki67       clone B56                    
Microelectrode Array (MEA) Recordings
 
     After 8 weeks of differentiation, BMPS were plated on 48-well MEA plates previously coated with Matrigel. During two weeks spontaneous electrical activity was recorded using the ‘Maestro’ MEA platform and Axion&#39;s Integraded Studio (AXIS) software [Axion Biosystems inc.; Atlanta, US]. Each well of the 48-well MEA plate contains 16 individual microelectrodes (˜40-50 μm diameter, center-to-center spacing 350 μm) with integrated ground electrodes, resulting in a total of 768 electrodes/plate. The ‘Maestro’ MEA platform has an integrated heating system, which can be controlled by AXIS software. All recordings were performed at a constant temperature of 37° C. Prior to a twenty minutes recording, the MEA plates were placed in the Maestro MEA platform and equilibrated for five min. AXIS software was used to control heating system and monitor the recordings, which includes simultaneously sampling of the channels at 12.5 kHz/channel with a gain of 1200× and a band pass filter of 200-5000 Hz. The recordings were converted into RAW files. After a recording the RAW-files were re-recorded with AXIS to convert the data into a spike file, which includes spike timing and profile information. A variable threshold spike detector was used for the spike-file, it was set at 6 times standard deviations of the rms-noise on each channel. The spike file was later used for data analysis with NeuroExplorer® [Nex Technologies, Madison (AL), US] to convert data into Microsoft Excel files. Using the function rate histogram, a summary of the spikes of all electrodes of one plate was put into one Excel sheet. Only electrodes that recorded activity higher than 0.05 spikes/sec at least once over the time measured were included for data analysis. 
     Statistical Analysis 
     Statistical analysis was performed using GraphPad InStat 3. The Dunnett&#39;s test was applied to all the experiments shown here that compare to a control group. Statistically significant values (p&lt;0.01) are marked with an asterisk (*). For myelination quantification at the different time points, a Kruskal-Wallis test was employed, statistical significance was considered for p values &lt;0.05. 
     REFERENCES 
     
         
         1. K. Y. Liu, M. King, P. S. Bearman. Social influence and the autism epidemic.  AJS  115, 1387-434 (2010). 
         2. M. Rutter. Incidence of autism spectrum disorders: changes over time and their meaning.  Acta. Paediatr.  94, 2-15 (2005). 
         3. S. K. Van Den Eeden, C. M. Tanner, A. L. Bernstein, R. D. Fross, A. Leimpeter, D. A. Bloch, L. M. Nelson. Incidence of Parkinson&#39;s disease: variation by age, gender, and race/ethnicity.  Am. J. Epidemiol.  157, 1015-22 (2003). 
         4. W, A. Kukull, R. Higdon, J. D. Bowen, W. C. McCormick, L. Teri, G. D. Schellenberg, G. van Belle, L. Jolley, E. B. Larson. Dementia and Alzheimer disease incidence: a prospective cohort study.  Arch. Neurol.  59, 1737-46 (2002). 
         5. C. Mo, A. J. Hannan, T. Renoir. Environmental factors as modulators of neurodegeneration: Insights from gene-environment interactions in Huntington&#39;s disease.  Neurosci. Biobehav. Rev.  52, 178-192 (2015). 
         6. S. Karama, S. Ducharme, J. Corley, F. Chouinard-Decorte, J. M. Starr, J. M. Wardlaw, M. E. Bastin, I. J. Deary. Cigarette smoking and thinning of the brain&#39;s cortex.  Mol. Psychiatry . In press (2015). 
         7. O. van de Rest, A. A. Berendsen, A. Haveman-Nies, L. C. de Groot. Dietary Patterns, Cognitive Decline, and Dementia: A Systematic Review.  Adv. Nutr.  13, 154-168. (2015) 
         8. L. Smirnova H. T. Hogberg, M. Leist and T. Hartung. Developmental neurotoxicity—challenges in the 21st century and in vitro opportunities.  ALTEX  31, 129-156 (2014), 
         9. T. Hartung. Look back in anger—what clinical studies tell us about preclinical work.  ALTEX.  30, 275-91 (2013) 
         10. T. Hartung. Food for thought . . . on cell culture.  ALTEX.  24, 143-52 (2007) 
         11. D. Huh, D. C. Leslie, B. D. Matthews, J. P. Fraser, S. Jurek, G. A. Hamilton, K. S. Thorneloe, M. A. McAlexander, D. E. Ingber. A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice.  Sci. Transl. Med.  7, 4(159):159ra147 (2012). 
         12. D. Pamies, T. Hartung, H. T. Hogberg. Biological and medical applications of a brain-on-a-chip.  Exp. Biol. Med.  239, 1096-107 (2014) 
         13. A. Agarwal, J. A. Goss, A. Cho, M. L. McCain, K. K. Parker. Microfluidic heart on a chip for higher throughput pharmacological studies.  Lab on a chip  13, 3599-3608 (2013). 
         14. H. T. Hogberg, J. Bressler, K. M. Christian, G. Harris, G. Makri, C. O&#39;Driscol, D. Pamies, L. Smirnova, Z. Wen, T. Hartung. Toward a 3D model of human brain development for studying gene/environment interactions.  Stem. Cell. Res . Ther. 4 Suppl 1:S4 (2013). 
         15. M. A. Lancaster, M. Renner, C. A. Martin, D. Wenzel, L. S. Bicknell, M. E. Hurles, T. Homfray, J. M. Penninger, A. P. Jackson, J. A. Knoblich. Cerebral organoids model human brain development and microcephaly.  Nature  19, 373-9 (2013). 
         16. Kadoshima T, Sakaguchi H, Nakano T, Soen M, Ando S, Eiraku M, Sasai Y. Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex.  Proc. Natd. Acad. Sci. USA.  110, 20284-9 (2013). 
         17. D. Huh, H. J. Kim, J. P. Fraser, D. E. Shea, M. Khan, A. Bahinski, G. A. Hamilton, D. E. Ingber. Microfabrication of human organs-on-chips.  Nat. Protoc.  8, 2135-57 (2013). 
         18. N. Aldpde, A. Bahinski, M. Daneshian, B. De Wever, E. Fritsche, A. Goldberg, J. Hansmann, T. Hartung, J. Haycock, H. Hogberg, L. Hoelting, J. M. Kelm, S. Kadereit, E. McVey, R. Landsiedel, M. Leist, M. Lubberstedt, F. Noor, C. Pellevoisin, D. Petersohn, U. Pfannenbecker, K. Reisinger, T. Ramirez, B. Rothen-Rutishauser, M. Schäfer-Korting, K. Zeilinger, M. G. Zurich. State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology.  ALTEX.  31, 441-77 (2014). 
         19. T. Hartung, J. Zurlo. Alternative approaches for medical countermeasures to biological and chemical terrorism and warfare.  ALTEX.  29, 251-60 (2012). 
         20. K. Takahashi, K. Tanabe, M. Ohnuki, M. Narita, T. Ichisaka, K. Tomoda, S. Yamanaka. Induction of pluripotent stem cells from adult human fibroblasts by defined factors.  Cell  131: 861-872 (2007). 
         21. J. Yu, M. A. Vodyanik, K. Smuga-Otto, J. Antosiewicz-Bourget, J. L. Frane, S. Tian, J. Nie, G. A. Jonsdottir, V. Ruotti, R. Stewart, I. I. Slukvin, J. A. Thomson. Induced pluripotent stem cell lines derived from human somatic cells.  Science  318: 1917-1920 (2007) 
         22. Y. Tsai, B. Lu, B. Bakondi, S. Girman, A. Sahabian, D. Sareen, C. N. Svendsen, S. Wang. Human iPSC-Derived Neural Progenitors Preserve Vision in an AMD-like Model.  Stem. Cells . In press (2015). 
         23. K. Nieweg, A. Andreyeva, B. van Stegen, G. Tanriöver, K. Gottmann. Alzheimer&#39;s disease-related amyloid-β induces synaptotoxicity in human iPS cell-derived neurons.  Cell. Death. Dis . In press. (2015) 
         24. S. Raitano, L. Ordovàs, L. De Muynck, W. Guo, I. Espuny-Camacho, M. Geraerts, S. Khurana, K. Vanuytsel, B. I. Tóth, T. Voets, R. Vandenberghe, T. Cathomen, L. Van Den Bosch, P. Vanderhaeghen, P. Van Damme, C. M. Verfaillie. Restoration of progranulin expression rescues cortical neuron generation in an induced pluripotent stem cell model of frontotemporal dementia.  Stem Cell Reports.  13, 16-24 (2015). 
         25. H. Monyer, R. Sprengel, R. Schoepfer, A. Herb, M. Higuchi, H. Lomeli, N. Bumashev, B. Sakmann, P. H. Seeburg. Heteromeric NMDA receptors: molecular and functional distinction of subtypes.  Science  256, 1217-1221 (1992). 
         26. X. Li, P. Jin. Roles of small regulatory RNAs in determining neuronal identity.  Nat. Rev. Neurosci.  11, 329-38 (2010). 
         27. C. Tarantino, G. Paolella, L. Cozzuto, G. Minopoli, L. Pastore, S. Parisi, T. Russo. miRNA 34a, 100, and 137 modulate differentiation of mouse embryonic stem cells.  FASEB Journal  24, 3255-3263 (2010). 
         28. D. Yang, T. Li, Y. Wang, Y. Tang, H. Cui, X. Zhang, D. Chen, N. Shen, W. Le W. miR-132 regulates the differentiation of dopamine neurons by directly targeting Nurr1 expression.  Journal of Cell Science  125, 1673-1682 (2012). 
         29. D. Edbauer, J. R. Neilson, K. A. Foster, C. F. Wang, D. P. Seeburg, M. N. Batterton, T. Tada, B. M. Dolan, P. A. Sharp, M. Sheng. Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132 . Neuron  65, 373-384 (2010). 
         30. S. U. Kim, F. A. McMorris, T. J. Sprinkle. Immunofluorescence demonstration of 2′:3′-cyclic-nucleotide 3′-phosphodiesterase in cultured oligodendrocytes of mouse, rat, calf and human.  Brain Res.  300, 195-9 (1984). 
         31. W. Deng, R. D. Poretz. Oligodendroglia in developmental neurotoxicity.  Neurotoxicology.  24, 161-78 (2003). 
         32. S. P. Fancy, J. R. Chan, S. E. Baranzini, R. J. Franklin, D. H. Rowitch. Myelin Regeneration: A recapitulation of development?  Annu. Rev. Neurosci.  34, 21-43 (2011) 
         33. M. E. Schwab. Functions of Nogo proteins and their receptors in the nervous system.  Nat. Rev. Neurosci.  11, 799-811 (2010). 
         34. D. H. Meijer, M. F. Kane, S. Mentha, H. Liu, E. Harrington, C. M. Taylor, C. D. Stiles, D. H. Rowitch. Separated at birth? The functional and molecular divergence of OLIG1 and OLIG2 . Nat. Rev. Neurosci.  13, 819-31 (2012). 
         35. Y. Yamaguchi, M. Miura. Programmed cell death in neurodevelopment.  Dev. Cell.  32, 478-90 (2015). 
         36. H. A. Juraver-Geslin, B. C. Durand. Early development of the neural plate: new roles for apoptosis and for one of its main effectors caspase-3 . Genesis.  53, 203-24 (2015). 
         37. A. K. Krug, S. Gutbier, L. Zhao, D. Pöltl, C. Kullmann, V. Ivanova, S. Förster, S. Jagtap, J. Meiser, G. Leparc, S. Schildknecht, M. Adam, K. Hiller, H. Farhan, T. Brunner, T. Hartung, A. Sachinidis, M. Leist. Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP(+).  Cell Death Dis.  5, e1222 (2014). 
         38. T. Nakano, S. Ando, N. Takata, M. Kawada, K. Muguruma, K. Sekiguchi, K. Saito, S. Yonemura, M. Eiraku, Y. Sasai. Self-formation of optic cups and storable stratified neural retina from human ESCs.  Cell Stem Cell.  14, 771-85 (2012) 
         39. M. Eiraku, N. Takata, H. Ishibashi, M. Kawada, E. Sakakura, S. Okuda, K. Sekiguchi, T. Adachi, Y. Sasai. Self-organizing optic-cup morphogenesis in three-dimensional culture.  Nature.  472, 51-6 (2012). 
         40. H. Suga, T. Kadoshima, M. Minaguchi, M. Ohgushi, M. Soen, T. Nakano, N. Takata, T. Wataya, K. Muguruma, H. Miyoshi, S. Yonemura, Y. Oiso, Y. Sasai. Self-formation of functional adenohypophysis in three-dimensional culture.  Nature.  480, 57-62 (2011). 
         41. E. van Vliet, S. Morath, C. Eskes, J. Linge, J. Rappsilber, P. Honegger, T. Hartung, S. Coecke. A novel in vitro metabolomics approach for neurotoxicity testing, proof of principle for methyl mercury chloride and caffeine.  Neurotoxicology.  29, 1-12 (2008). 
         42. J. Kim, K. Inoue, J. Ishii, W. B. Vanti, S. V. Voronov, E. Murchison, G. Hannon, A. Abeliovich. A MicroRNA feedback circuit in midbrain dopamine neurons.  Science  317, 1220-1224 (2007). 
         43. C. Wiese, A. Rolletschek, G. Kania, P. Blyszczuk, K. V. Tarasov, Y. Tarasova, R. P. Wersto, K. R. Boheler, A. M. Wobus. Nestin expression—a property of multi-lineage progenitor cells?  Cell. Mol. Life. Sci.  61, 2510-22 (2004). 
         44. C. Lépinoux-Chambaud, J. Eyer. Review on intermediate filaments of the nervous system and their pathological alterations. Histochem. Cell. Biol. 140, 13-22 (2013). 
         45. J. Park, B. K. Lee, G. S. Jeong, J. K. Hyun, C. J. Lee, S. H. Lee. Three-dimensional brain-on-a-chip with an interstitial level of flow and its application as an in vitro model of Alzheimer&#39;s disease.  Lab Chip.  15, 141-50 (2015). 
         46. J. P. Dollé, B. Morrison, R. S. Schloss, M. L. Yarmush. Brain-on-a-chip microsystem for investigating traumatic brain injury: Axon diameter and mitochondrial membrane changes play a significant role in axonal response to strain injuries.  Technology  ( Singap. World. Sci .). 2,106 (2014). 
         47. S. J. Mullett, D. A. Hinkle. DJ-1 knock-down in astrocytes impairs astrocyte-mediated neuroprotection against rotenone.  Neurobiol. Dis.  33, 28-36 (2009). 
         48. Y. Shinozaki, M. Nomura, K. Iwatsuki, Y. Moriyama, C. Gachet, S. Koizumi. Microglia trigger astrocyte-mediated neuroprotection via purinergic gliotransmission.  Sci. Rep.  4, 4329 (2014). 
         49. D. Aguirre-Rueda, S, Guerra-Ojeda, M. Aldasoro, A. Iradi, E. Obrador, A. Ortega, M. D. Mauricio, J. M. Vila, S. L. Valles. Astrocytes protect neurons from Aβ1-42 peptide-induced neurotoxicity increasing TFAM and PGC-1 and decreasing PPAR-γ and SIRT-1 . Int. J. Med. Sci.  12, 48-56. (2015). 
         50. R. Sattler, M. Tymianski. Molecular mechanisms of glutamate receptormediated excitotoxic neuronal cell death.  Mol. Neurobiol.  24, 107-129 (2001). 
         51. Y. Shao, M. Gearing, S. S. Mirra. Astrocyte-apolipoprotein E associations in senile plaques in Alzheimer disease and vascular lesions: a regional immunohistochemical study.  J. Neuropathol. Exp. Neurol.  56, 376-381 (1997) 
         52. C. Schwab, P. L. McGeer. Inflammatory aspects of Alzheimer disease and other neurodegenerative disorders.  J. Alzheimers. Dis.  13, 359-369 (2008). 
         53. P. Damier, E. C. Hirsch, P. Zhang, Y. Agid, F. Javoy-Agid. Glutathione peroxidase, glial cells and Parkinson&#39;s disease.  Neuroscience  52, 1-6 (1993). 
         54. C. Xie, Y. Q. Liu, Y. T. Guan, G. X. Zhang. Induced Stem Cells as a Novel Multiple Sclerosis Therapy.  Curr Stem Cell Res Ther . In press (2015). 
         55. S. Wang, J. Bates, X. Li, S. Schanz, D. Chandler-Militello, C. Levine, N. Maherali, L. Studer, K. Hochedlinger, M. Windrem, S. A. Goldman. Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination.  Cell Stem Cell.  12, 252-64 (2013) 
         56. M. Pinto, S. Dobson. BK and JC virus: a review.  J. Infect.  68 Suppl 1:S2-8 (2014). 
         57. X. B. Liu, Y. Shen, J. M. Plane, W. Deng. Vulnerability of premyelinating oligodendrocytes to white-matter damage in neonatal brain injury.  Neurosci. Bull.  29, 229-38 (2013). 
         58. G. Bartzokis. Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer&#39;s disease.  Neurobiol. Aging.  25, 5-18 (2004). 
         59. H. Okamoto, T. Miki, K. Y. Lee, T. Yokoyama, H. Kuma, Z. Y. Wang, H. Gu, H. P. Li, Y. Matsumoto, S. Irawan, K. S. Bedi, Y. Nakamura, Y. Takeuchi. Oligodendrocyte myelin glycoprotein (OMgp) in rat hippocampus is depleted by chronic ethanol consumption.  Neurosci. Lett.  406, 76-80 (2006). 
         60. T. W. Bouldin, G. Samsa, T. S. Earnhardt, M. R. Krigman. Schwann cell vulnerability to demyelination is associated with intemodal length in tellurium neuropathy. J.  Neuropathol. Exp. Neurol.  47, 41-47 (1988). 
         61. P. David, K. Subramaniam. Prenatal alcohol exposure and early postnatal changes in the developing nerve-muscle system.  Birth Defects Res. A. Clin. Mol. Teratol.  73, 897-903 (2005). 
         62. G. J. Harry, A. D. Toews, M. R. Krigman, P. Morell. The effect of lead toxicity and milk deprivation of myelination in the rat.  Toxicol. Appl. Pharmacol.  77, 458-464 (1985). 
         63. S. J. Rothenberg, A. Poblano, S. Garza-Morales. Prenatal and perinatal low level lead exposure alters brainstem auditory evoked responses in infants.  Neurotoxicology  15, 695-699 (1994). 
         64. E. Tiffany-Castiglioni, J. Zmudzki, G. R. Bratton. Cellular targets of lead neurotoxicity: in vitro models.  Toxicology  42, 303-315 (1986). 
         65. E. Tiffany-Castiglioni. Cell culture models for lead toxicity in neuronal and glial cells.  Neurotoxicology.  14, 513-36 (1993). 
         66. J. Parkinson. An essay on the shaking palsy. 1817. J. Neuropsychiatry  Clin. Neurosci.  14:223-36 (2002) 
         67. K. R. Chaudhuri, P. Odin. The challenge of non-motor symptoms in Parkinson&#39;s disease.  Prog. Brain. Res.  184, 325-41 (2010). 
         68. P. McGonigle. Animal models of CNS disorders.  Biochem. Pharmacol.  87, 140-9 (2014). 
         69. K. Tieu. A guide to neurotoxic animal models of Parkinson&#39;s disease. Cold. Spring. Harb. Perspect. Med. In press (2011). 
         70. S. E. Cavanaugh, J. J. Pippin, N. D. Barnard. Animal models of Alzheimer disease: historical pitfalls and a path forward.  ALTEX.  31, 279-302 (2014). 
         71. A. Pombero, C. Bueno, L. Saglietti, M. Rodenas, J. Guimera, A. Bulfone, S. Martinez. Pallial origin of basal forebrain cholinergic neurons in the nucleus basalis of Meynert and horizontal limb of the diagonal band nucleus.  Development.  138, 4315-26 (2011). 
         72. H. McCann, C. H. Stevens, H. Cartwright, G. M. Halliday. α-Synucleinopathy phenotypes.  Parkinsonism. Relat. Disord.  20 Suppl 1, S62-7 (2014). 
         73. V. N. Uversky. A protein-chameleon: conformational plasticity of alphasynuclein, a disordered protein involved in neurodegenerative disorders.  J. Biomol. Struct. Dyn.  21, 211-34 (2003) 
         74. G. A. Petsko and D. Ringer. Ice cleaved alpha-synuclein a biomarker. Patent WO2012061786 A1. (2012) 
         75. Wen Z, Nguyen H N, Guo Z, Lalli M A, Wang X, Su Y, Kim N S, Yoon K J, Shin J, Zhang C, Makri G, Nauen D, Yu H, Guzman E, Chiang C H, Yoritomo N, Kaibuchi K, Zou J, Christian K M, Cheng L, Ross C A, Margolis R L, Chen G, Kosik K S, Song H, Ming G L. Synaptic dysregulation in a human iPS cell model of mental disorders.  Nature.  2014 Nov. 20; 515(7527):414-8. 
         76. P. Chomczynski, N. Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.  Ana.l Biochem.  162, 156-9 (1987). 
         77. L. Smirnova, A. E. M. Seiler, A. Luch. microRNA profiling as tool for developmental neurotoxicity testing (DNT).  Toxicol.  64:20.9.1-20.9.22, 2015 
         78. K. J. Livak, T. D. Schmittgen. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method.  Methods.  25, 402-8 (2001). 
         79. Nave, K. A. Myelination and support of axonal integrity by glia.  Nature  468, 244-252, (2010). 
         80. Saab, A. S., Tzvetanova, I. D. &amp; Nave, K. A. The role of myelin and oligodendrocytes in axonal energy metabolism.  Current opinion in neurobiology  23, 1065-1072, (2013). 
         81. Pardridge, W. M. Crossing the blood brain barrier: are we getting it right?  Drug Disc. Today  January 1; 6(1): 1-2, (2001). 
         82. Kerman, B. E. et al.  In vitro myelin formation using embryonic stem cells. Development  142, 2213-2225, (2015) 
         83. Gaj T, Gersbach C A, Barbas C F 3rd. ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering.  Trends Biotechnol . July; 31(7):397-405, (2013). 
         84. Hockemeyer D, Soldner F, Beard C, Gao Q, Mitalipova M, DeKelver R C, Katibah G E, Amora R, Boydston E A, Zeitler B, Meng X, Miller J C, Zhang L, Rebar E J, Gregory P D, Urnov F D, Jaenisch R. Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases.  Nat Biotechnol . September; 27(9):851-7, (2009). 
         85. Hockemeyer D, Wang H, Kiani S, Lai C S, Gao Q, Cassady J P, Cost G J, Zhang L, Santiago Y, Miller J C, Zeitler B, Cherone J M, Meng X, Hinkley S J, Rebar E J, Gregory P D, Urnov F D, Jaenisch R. Genetic engineering of human pluripotent cells using TALE nucleases.  Nat Biotechnol . July 7; 29(8):731-4, (2011). 
         86. Mali P, Aach J, Stranges P B, Esvelt K M, Moosburner M, Kosuri S, Yang L, Church G M. CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering.  Nat Biotechnol . September; 31(9):833-8, (2013). 
         87. Chang N, Sun C, Gao L, Zhu D, Xu X, Zhu X, Xiong J W, Xi J J. Genome editing with RNA-guided Cas9 nuclease in zebrafish embryos.  Cell Res . April; 23(4):465-72, (2013). 
         88. Cong L, Ran F A, Cox D, Lin S, Barretto R, Habib N, Hsu P D, Wu X, Jiang W, Marraffini L A, Zhang F. Multiplex genome engineering using CRISPR/Cas systems.  Science . February 15; 339(6121):819-23, (2013). 
         89. Ran F A, Hsu P D, Wright J, Agarwala V, Scott D A, Zhang F. Genome engineering using the CRISPR-Cas9 system.  Nat Protoc . November; 8(11):2281-308, (2013). 
         90. Kim W R, Sun W. 2011. Programmed cell death during postnatal development of the rodent nervous system.  Development, growth  &amp;  differentiation  53: 225-235, (2011). 
       
    
     EQUIVALENTS 
     Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.