bluuebunny/crossref_metadata_2025 huggingface dataset:
Histone H3 lysine 9 acetylation pattern suggests that X and B chromosomes are silenced during entire male meiosis in a grasshopper
Authors: Cabrero J. , Teruel M. , Carmona F.D. , Jiménez R. , Camacho J.P.M.
Published: December 2007

The facultative heterochromatic X chromosome in leptotene spermatocytes of the grasshopper Eyprepocnemis plorans showed marked hypoacetylation for lysine 9 in the H3 histone (H3-K9) with no sign of histone H2AX phosphorylation. Since H3-K9 hypoacetylation precedes the meiotic appearance of phosphorylated H2AX (γ-H2AX), which marks the beginning of recombinational DNA double-strand breaks (DSBs), it seems that meiotic sex-chromosome inactivation (MSCI) in this grasshopper occurs prior to the beginning of recombination and hence synapsis (which in this species begins later than recombination). In addition, all constitutively heterochromatic chromosome regions harbouring a 180-bp tandem-repeat DNA and rDNA (B chromosomes and pericentromeric regions of A chromosomes) were H3-K9 hypoacetylated at early leptotene even though they will synapse at subsequent stages. This also suggests that meiotic silencing in this grasshopper might be independent of synapsis. The H3-K9 hypoacetylated state of facultative and constitutive heterochromatin persisted during subsequent meiotic stages and was even apparent in round spermatids. Finally, the fact that B chromosomes are differentially hypoacetylated in testis and embryo interphase cells suggests that they might be silenced early in development and remain this way for most (or all) life-cycle stages.
Physical mapping of rDNA and satDNA in A and B chromosomes of the grasshopper Eyprepocnemis plorans from a Greek population
Authors: Abdelaziz M. , Teruel M. , Chobanov D. , Camacho J.P.M. , Cabrero J.
Published: December 2007

Adult males and females of the grasshopper Eyprepocnemis plorans from a Greek population were analysed by C-banding, silver impregnation and double FISH for two DNA probes, i.e. ribosomal DNA (rDNA) and a 180-bp tandem repeat DNA (satDNA). This population shows characteristics of rDNA location in A chromosomes that are intermediate between those previously reported for eastern (Caucasus) and western (Spain and Morocco) populations. The four rDNA clusters revealed by FISH in chromosomes X, 9, 10 and 11 in Greek specimens imply two more than the two observed in chromosomes 9 and 11 in the Caucasus, but less than the 12 observed in all chromosomes in Morocco. Remarkably, the X chromosome bears one of the new rDNA locations in Greece with respect to the Caucasus, but it appears to be inactive, in contrast to X chromosomes in western populations, which are usually active. B chromosomes were very frequent in the Greek population, and three variants differing in size were observed, all of these being largely composed of rDNA, with the exception of a small pericentromeric satDNA cluster. The high B frequency suggests that B chromosomes in this population might behave parasitically, in resemblance to Bs in western populations.
Molecular characterisation and chromosomal localisation of a telomere-like repetitive DNA sequence highly enriched in the C genome of Brassica
Authors: Galvão Bezerra dos Santos K. , Becker H.C. , Ecke W. , Bellin U.
Published: December 2007

The aim of this work was to find C genome specific repetitive DNA sequences able to differentiate the homeologous A (B. rapa) and C (B. oleracea) genomes of Brassica, in order to assist in the physical identification of B. napus chromosomes. A repetitive sequence (pBo1.6) highly enriched in the C genome of Brassica was cloned from B. oleracea and its chromosomal organisation was investigated through fluorescent in situ hybridisation (FISH) in B. oleracea (2n = 18, CC), B. rapa (2n = 20, AA) and B. napus (2n = 38, AACC) genomes. The sequence was 203 bp long with a GC content of 48.3%. It showed up to 89% sequence identity with telomere-like DNA from many plant species. This repeat was clearly underrepresented in the A genome and the in situ hybridisation showed its B. oleracea specificity at the chromosomal level. Sequence pBo1.6 was localised at interstitial and/or telomeric/subtelomeric regions of all chromosomes from B. oleracea, whereas in B. rapa no signal was detected in most of the cells. In B. napus 18 to 24 chromosomes hybridised with pBo1.6. The discovery of a sequence highly enriched in the C genome of Brassica opens the opportunity for detailed studies regarding the subsequent evolution of DNA sequences in polyploid genomes. Moreover, pBo1.6 may be useful for the determination of the chromosomal location of transgenic DNA in genetically modified oilseed rape.
A neocentromere derived from a supernumerary marker deleted from the long arm of chromosome 6
Authors: Qin N. , Bartley J. , Wang J.-C. , Warburton P.E.
Published: December 2007

Parental chromosome studies were referred to us after initial finding of a balanced translocation involving chromosomes 4 and 15 in their phenotypically abnormal male child (cytogenetic analysis was done at another laboratory). In addition to the same 4;15 translocation, the father also had an interstitial deletion of the long arm of one chromosome 6 and a marker chromosome. In this article, we report a neocentromere on this marker, which was determined to be composed of chromosome 6 material by FISH. The child’s karyotype was re-interpreted to be unbalanced due to the presence of the abnormal chromosome 6, but without the marker. The clinical phenotype associated with the interstitial deletion of chromosome 6 is also reported.
Two independent chromosomal rearrangements, a very small (550 kb) duplication of the 7q subtelomeric region and an atypical 17q11.2 (NF1) microdeletion, in a girl with neurofibromatosis
Authors: Bartsch O. , Vlčková Z. , Erdogan F. , Ullmann R. , Novotná D. , Spiegel M. , Beyer V. , Haaf T. , Zechner U. , Seemanová E.
Published: December 2007

Most patients with neurofibromatosis (NF1) are endowed with heterozygous mutations in the NF1 gene. Approximately 5% show an interstitial deletion of chromosome 17q11.2 (including NF1) and in most cases also a more severe phenotype. Here we report on a 7-year-old girl with classical NF1 signs, and in addition mild overgrowth (97th percentile), relatively low OFC (10th–25th percentile), facial dysmorphy, hoarse voice, and developmental delay. FISH analysis revealed a 17q11.2 microdeletion as well as an unbalanced 7p;13q translocation leading to trisomy of the 7q36.3 subtelomeric region. The patient’s mother and grandmother who were phenotypically normal carried the same unbalanced translocation. The 17q11.2 microdeletion had arisen de novo. Array comparative genomic hybridization (CGH) demonstrated gain of a 550-kb segment from 7qter and loss of 2.5 Mb from 17q11.2 (an atypical NF1 microdeletion). We conclude that the patient’s phenotype is caused by the atypical NF1 deletion, whereas 7q36.3 trisomy represents a subtelomeric copy number variation without phenotypic consequences. To our knowledge this is the first report that a duplication of the subtelomeric region of chromosome 7q containing functional genes (FAM62B, WDR60, and VIPR2) can be tolerated without phenotypic consequences. The 17q11.2 microdeletion (containing nine more genes than the common NF1 microdeletions) and the 7qter duplication were not accompanied by unexpected clinical features. Most likely the 7qter trisomy and the 17q11.2 microdeletion coincide by chance in our patient.
Trisomy of medial 15q as result of an analphoid supernumerary ring chromosome detected by CGH and FISH
Authors: Constantinou M. , Płowás I. , Kałużewski B.
Published: December 2007

We report a 21-year-old patient with a de novo mosaic, analphoid ring of chromosome 15q22.2→q24.1. The clinical features of this patient are mild and include tall stature, obesity, striae distensae in the hypogastrium, malocclusion and bilateral gynecomastia with scarce glandular tissue. M-FISH and FISH using a chromosome 15 painting probe indicated that the ring is of chromosome 15 origin. Further CGH analysis and FISH with the PML locus-specific probe demonstrated that the extra material derived from the medial part of the long arm of chromosome 15, including two bands, q22 and q23. Additionally, FISH with BAC probes specific for 15q allowed for a localization of the breakpoints at 15q22.2 and 15q24.1, distal to clones RP11-30M4 and RP11-500O23 respectively. We discuss the relationship between the patient’s genotype and phenotype comparing it to reported cases of trisomy of medial 15q.
Essentialism, Power, and the Representation of Social Categories: A Folk Sociology Perspective
Authors: Mahalingam Ramaswami
Published: December 2007

This paper synthesizes two perspectives on essentialism: cognitive and social. The cognitive essentialist perspective argues that our bias to appeal to the psychological belief that categories have innate essences enables us to make inferences about social categories such as race, caste, and gender. The social essentialist perspective argues that essentialist thinking serves the needs of those in power to justify existing social and economic hierarchies. Examining the relationship between essentialism and power, this paper expands the framework for folk sociology, incorporating cognitive and social essentialist accounts to examine folk theories of social differences between caste, race, gender, and class, with a particular emphasis on social marginality and cultural narratives. Further, this paper discusses the relevance of the folk sociology perspective to the study of children’s emerging understanding of their social world.
Bounded Rationality, Emotions and Older Adult Decision Making: Not So Fast and Yet So Frugal
Authors: Hanoch Yaniv , Wood Stacey , Rice Thomas
Published: December 2007

Herbert Simon’s work on bounded rationality has had little impact on researchers studying older adults’ decision making. This omission is surprising, as human constraints on computation and memory are exacerbated in older adults. The study of older adults’ decision-making processes could benefit from employing a bounded rationality perspective, but any such attempt must take into account the role that emotions play in older adults’ information processing, memory, and attention allocation. This is especially the case because older adults show relatively less decrements in performance when tasks are imbedded in or laden with emotional stimuli, and they exhibit a greater tendency to rely on emotional information. We examine recent work on bounded rationality and studies investigating older adults’ utilization of, and attention to, emotional information, with the aim of creating a framework that captures the mechanisms underlying older adults’ decision making.
Cerebellar Granule Cell Migration and the Effects of Alcohol
Authors: Jiang Yulan , Kumada Tatsuro , Cameron D. Bryant , Komuro Hitoshi
Published: December 2007

In the developing brain the majority of neurons migrate from their birthplace to their final destination. This active movement is essential for the formation of cortical layers and nuclei. The impairment of migration does not affect the viability of neurons but often results in abnormal differentiation. The proper migration of neurons requires the orchestrated activities of multiple cellular and molecular events, such as pathway selection, the activation of specific receptors and channels, and the assembly and disassembly of cytoskeletal components. The migration of neurons is very vulnerable to exposure to environmental toxins, such as alcohol. In this article, we will focus on recent developments in the migration of cerebellar granule cells. First, we will describe when, where and how granule cells migrate through different cortical layers to reach their final destination. Second, we will present how internal programs control the sequential changes in granule cell migration. Third, we will review the roles of external guidance cues and transmembrane signals in granule cell migration. Finally, we will reveal mechanisms by which alcohol exposure impairs granule cell migration.
Role of Intermediate Progenitor Cells in Cerebral Cortex Development
Authors: Pontious Adria , Kowalczyk Tom , Englund Chris , Hevner Robert F.
Published: December 2007

Intermediate progenitor cells (IPCs) are a type of neurogenic transient amplifying cells in the developing cerebral cortex. IPCs divide symmetrically at basal (abventricular) positions in the neuroepithelium to produce pairs of new neurons or, in amplifying divisions, pairs of new IPCs. In contrast, radial unit progenitors (neuroepithelial cells and radial glia) divide at the apical (ventricular) surface and produce only single neurons or single IPCs by asymmetric division, or self-amplify by symmetric division. Histologically, IPCs are most prominent during the middle and late stages of neurogenesis, when they accumulate in the subventricular zone, a progenitor compartment linked to the genesis of upper neocortical layers (II–IV). Nevertheless, IPCs are present throughout cortical neurogenesis and produce neurons for all layers. In mice, changes in the abundance of IPCs caused by mutations of Pax6, Ngn2, Id4 and other genes are associated with parallel changes in cortical thickness but not surface area. In gyrencephalic brains, IPCs may play broader roles in determining not only laminar thickness, but also cortical surface area and gyral patterns. We propose that regulation of IPC genesis and amplification across developmental stages and regional subdivisions modulates laminar neurogenesis and contributes to the cytoarchitectonic differentiation of cortical areas.
Functions of Rac GTPases during Neuronal Development
Authors: de Curtis Ivan
Published: December 2007

The small GTPases of the Rho family are important regulators of the actin cytoskeleton and are critical for several aspects of neuronal development including the establishment of neuronal polarity, extension of axon and dendrites, neurite branching, axonal navigation and synapse formation. The aim of this review is to present evidence supporting the function of Rac and Rac-related proteins in different aspects of neuronal maturation, based on work performed with organisms including nematodes, Drosophila, Xenopus and mice, and with primary cultures of developing neurons. Three of the 4 vertebrate Rac-related genes, namely Rac1, Rac3 and RhoG, are expressed in the nervous system, and several data support an essential role of all 3 GTPases in distinct aspects of neuronal development and function. Two important points emerge from the analysis presented: highly homologous Rac-related proteins may perform different functions in the developing nervous system; on the other hand, the data also indicate that similar GTPases may perform redundant functions in vivo.
Function of PTEN during the Formation and Maintenance of Neuronal Circuits in the Brain
Authors: van Diepen Michiel T. , Eickholt Britta J.
Published: December 2007

PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a tumor suppressor that can inhibit proliferation and migration and controls apoptosis in a number of cell types, mainly through inhibition of the phosphoinositide 3-kinase (PI3K) signaling pathway. Patients carrying inactivating mutations of PTEN show a prevalence to develop tumors that can coincide with neurological defects such as mental retardation, ataxia and seizures. A number of in vitro and in vivo studies were instrumental in uncovering a direct correlation between deregulated PI3K/PTEN signaling and changes in neuronal morphogenesis, which is likely to have profound bearings upon the pathogenesis of neurological symptoms. This review outlines recent work on the function of PTEN during vertebrate brain development and the current understanding of the signaling pathways downstream of PTEN that control neuronal connectivity in the brain.
How Neuronal Migration Contributes to the Morphogenesis of the CNS: Insights from the Zebrafish
Authors: Mione Marina , Baldessari Danila , Deflorian Gianluca , Nappo Gilda , Santoriello Cristina
Published: December 2007

We used transgenic zebrafish expressing GFP or YFP in subpopulations of neurons to study the migration, homing process and axon extension of groups of CNS neurons in different regions of the zebrafish brain. We found that extensive migration takes place at all levels of the CNS and gives rise to nuclei or cell populations with specific identities. Here, we describe 4 previously unknown or only partially characterized migratory events taking place in the zebrafish telencephalon and rhombic lip, using 3 different transgenic lines, and identify the phenotypes of the cells undertaking these migrations. The migration of a subgroup of mitral cell precursors from the dorsocaudal telencephalon to the olfactory bulb, visualized in the tg(tbr1:YFP) transgenic line, is coupled with morphogenetic transformation of the dorsal telencephalon. The tg(1.4dlx5a-6a:GFP) transgenic line provides a means to analyze the migration of GABAergic interneurons from the ventral to the dorsal telencephalon, thus extending the occurrence of this migration to another vertebrate. The tg(Xeom:GFP) transgenic line provides the first demonstration of the dorsoventral migration of glutamatergic septal neurons, present in mammals and now described in fish, thus reconciling the contrasting evidence of dorsal patterning genes (tbr1, eomes) expressed in a ventral cell population. Furthermore, migration studies in the tg(1.4dlx5a-6a:GFP) and tg(Xeom:GFP) lines help determine the origin of 2 important cell populations in the fish cerebellum: projection neurons and Purkinje cells. These examples reinforce the concept that migratory events contribute to the distribution of cell types with diverse identities through the CNS and that zebrafish transgenic lines represent excellent tools to study these events.
The Potential Role of Cyclin-Dependent Kinase 5 in Focal Cortical Dysplasia
Authors: Sen Arjune , Thom Maria , Nikolić Margareta , Sisodiya Sanjay M.
Published: December 2007

Focal cortical dysplasia (FCD) is the most common malformation of cortical development found in epilepsy surgical series. Characterised by cortical mislamination, dysplastic neurons and, in a subgroup of cases, balloon cells, FCD is potently epileptogenic. Despite decades of study, the underlying aetiology of FCD remains uncertain and research has been hampered by the lack of a good animal model in which to simulate the condition. In this article we review some of the potential molecular mechanisms that might underpin human FCD. In particular we examine the potential role of cyclin-dependent kinase 5 and its principal activator p35 in FCD and estimate the contribution that deregulation of cyclin-dependent kinase 5 might make to the pathogenesis of this condition.
Migratory Behavior of Presumptive Interneurons Is Affected by AMPA Receptor Activation in Slice Cultures of Embryonic Mouse Neocortex
Authors: Yozu Masato , Tabata Hidenori , König Norbert , Nakajima Kazunori
Published: December 2007

It has been reported that functional α-amino-3-hydroxy-5-methyl-isoxazolpro-prionic acid (AMPA) receptors permeable to calcium are already expressed by tangentially migrating prospective interneurons in the developing rodent cerebral cortex. However, the role of these receptors is not yet fully understood. To examine the effect of activation of AMPA receptors on tangential migration, we exposed migrating prospective interneurons derived from the medial ganglionic eminence (MGE) to AMPA in slice cultures and performed time lapse imaging. In the neocortex, a subpopulation of MGE-derived cells stopped migration or changed the direction of migration in response to AMPA in a dose-dependent manner. In contrast, neither MGE-derived cells migrating in the subcortical territory nor radially migrating cells in the neocortex were affected by exposure to AMPA. Transfection of dominant-negative AMPA receptor subunit GluR1 to the tangentially migrating cells prevented the effects of AMPA on migration. This study provides evidence that the activation of AMPA receptors can directly affect tangential migration in the neocortical part of telencephalic slice cultures.
Stromal-Derived Factor 1 Signalling Regulates Radial and Tangential Migration in the Developing Cerebral Cortex
Authors: Liapi Anastasia , Pritchett James , Jones Owen , Fujii Nobutaka , Parnavelas John G. , Nadarajah Bagirathy
Published: December 2007

Stromal-derived factor 1 (SDF-1), a known chemoattractant, and its receptor CXCR4 are widely expressed in the developing and adult cerebral cortex. Recent studies have highlighted potential roles for SDF-1 during early cortical development. In view of the current findings, our histological analysis has revealed a distinct pattern of SDF-1 expression in the developing cerebral cortex at a time when cell proliferation and migration are at peak. To determine the role of chemokine signalling during early cortical development, embryonic rat brain slices were exposed to a medium containing secreted SDF-1 to perturb the endogenous levels of chemokine. Alternatively, brain slices were treated with 40 µM of T140 or AMD3100, known antagonists of CXCR4. Using these experimental approaches, we demonstrate that chemokine signalling is imperative for the maintenance of the early cortical plate. In addition, we provide evidence that both neurogenesis and radial migration are concomitantly regulated by this signalling system. Conversely, interneurons, although not dependent on SDF-1 signalling to transgress the telencephalic boundary, require the chemokine to maintain their tangential migration. Collectively, our results demonstrate that SDF-1 with its distinct pattern of expression is essential and uniquely positioned to regulate key developmental events that underlie the formation of the cerebral cortex.
Nocodazole-Induced Changes in Microtubule Dynamics Impair the Morphology and Directionality of Migrating Medial Ganglionic Eminence Cells
Authors: Baudoin Jean-Pierre , Alvarez Chantal , Gaspar Patricia , Métin Christine
Published: December 2007

We have shown previously that actomyosin contractility plays an important role in controlling nuclear movements in future interneurons born in the medial ganglionic eminence (MGE) [Bellion et al.: J Neurosci 2005;25:5691–5699]. Because microtubules are known to control the structural and motile properties of migrating neurons, we asked whether alterations in the dynamic instability of microtubules would impair MGE cell migration. Migration was analyzed in flat cocultures in which green-fluorescent-protein-expressing MGE cells migrate on cortical cells from their explant of origin. A low (100 nM) concentration of nocodazole shortened the leading process of MGE cells that nevertheless continued to migrate at the same rate but frequently changed their direction of migration relative to control cells. MGE cells treated with a higher (1 µM) concentration of nocodazole that strongly destabilized microtubules took on multipolar morphology. They extended thin and labile processes. MGE cells no longer exhibited directional migration and migration velocity slowed 2-fold. These results suggest that microtubule stability is crucial for maintaining polarity and controlling the directional migration of MGE cells, whereas additional mechanisms are required to control cell motility.
The Role of DCX and LIS1 in Migration through the Lateral Cortical Stream of Developing Forebrain
Authors: Bai Jilin , Ramos Raddy L. , Paramasivam Murugan , Siddiqi Faez , Ackman James B. , LoTurco Joseph J.
Published: December 2007

During forebrain development the lateral cortical stream (LCS) supplies neurons to structures in the ventral telencephalon including the amygdala and piriform cortex. In the current study, we used spatially directed in utero electroporation and RNAi to investigate mechanisms of migration to the ventral telencephalon. Cells labeled by in utero electroporation of the lateral ventricular zone migrated into the LCS, and entered the lateral neocortex, piriform cortex and amygdala, where they differentiated primarily as pyramidal neurons. RNAi of DCX or LIS1 disrupted migration into amygdala and piriform cortex and caused many neurons to accumulate in the external and amygdalar capsules. RNAi of LIS1 and DCX had similar as well as distinguishable effects on the pattern of altered migration. Combinatorial RNAi of LIS1 and DCX further suggested interaction in the functions of LIS1 and DCX on the morphology and migration of migrating neurons in the LCS. Together, these results confirm that the LCS contributes pyramidal neurons to ventral forebrain structures and reveals that DCX and LIS1 have important functions in this major migratory pathway in the developing forebrain.
Genetic Enhancement of the Lis1+/– Phenotype by a Heterozygous Mutation in the Adenomatous Polyposis Coli Gene
Authors: Hebbar Sachin , Guillotte Aimee M. , Mesngon Mariano T. , Zhou Qin , Wynshaw-Boris Anthony , Smith Deanna S.
Published: December 2007

Hemizygous Lis1 mutations cause type 1 lissencephaly, a neuronal migration disorder in humans. The Lis1+/– mouse is a model for lissencephaly; mice exhibit neuronal migration defects but are viable and fertile. On an inbred genetic background, 20% of Lis1+/– mice develop hydrocephalus and die prematurely. Lis1 functions with the microtubule motor cytoplasmic dynein. Because dynactin, a dynein regulator, interacts with end-binding protein 1 (EB1) and β-catenin, two known binding partners of the adenomatous polyposis coli (APC) protein, we looked for a genetic interaction between Lis1 and APC. Mice with a heterozygous truncating mutation in APC (Min mutation) do not exhibit neuronal migration defects or develop hydrocephalus. However, the presence of the APC mutation increases the migration deficit and the incidence of hydrocephalus in Lis1+/– animals. Lis1 and dynein distribution is altered in cells derived from Min mice, and both Lis1 and dynein interact with the C terminus of APC in vitro. Together, our findings point to a previously unknown interaction between APC and Lis1 during mammalian brain development.
Alternative Transcripts of Dclk1 and Dclk2 and Their Expression in Doublecortin Knockout Mice
Authors: Phan Dinh Tuy Françoise , Saillour Yoann , Kappeler Caroline , Chelly Jamel , Francis Fiona
Published: December 2007

The doublecortin (DCX) gene, mutated in X-linked human lissencephaly, has 2 close paralogs, doublecortin-like kinase 1 and 2 (Dclk1 and 2). In this study we attempted to better understand the dramatic differences between human and mouse DCX/Dcx-deficient phenotypes, focusing on the Dclk genes which are likely to compensate for Dcx function in the mouse. Using sequence database screens, Northern blot analyses and in situ hybridization experiments, we characterized the developmental transcripts of Dclk1 and 2, questioning their conservation between mouse and human, and their similarity to Dcx. Like Dcx, Dcx-like transcripts of the Dclk1 gene are expressed in postmitotic neurons in the developing cortex. No changes of expression were observed at the RNA level for these transcripts in Dcx knockout mice. However, a minor change in expression at the protein level was detected. The Dclk2 gene is less well characterized than Dclk1 andwe show here that it is expressed both in proliferating cells and postmitotic neurons, with a notably strong expression in the ventral telencephalon. No major differences in Dclk2 expression at the RNA and protein levels were identified comparing Dcx knockout and wild-type brains. We also analyzed Dclk1 and 2 expression in the hippocampal CA3 region which, unlike the neocortex, is abnormal in Dcx knockout mice. Interestingly, each transcript was expressed in CA3 neurons, including in the heterotopic pyramidal layer of Dcx knockout animals, but is presumably not able to compensate for a lack of Dcx. These results, in addition to characterizing the transcript diversity of an important family of genes, should facilitate further studies of compensation in Dcx-deficient mice.
Doublecortin Supports the Development of Dendritic Arbors in Primary Hippocampal Neurons
Authors: Cohen Dror , Segal Menahem , Reiner Orly
Published: December 2007

Doublecortin (DCX) is a microtubule-associated protein necessary for neuronal migration. In spite of its ubiquitous distribution in dendrites, its possible role in dendrite development has not yet been documented. The present study examined the effects of different expression levels of DCX on the arborization of dendrites in cultured hippocampal neurons. Reduced expression of DCX following RNAi transfection resulted in reduced branch points, total length and complexity of the dendrites. Overexpression of DCX resulted in an increase in branch points and complexity of the dendrites. In contrast to control green fluorescent protein cells, DCX-overexpressing cells maintained highly branched and complex dendritic trees when subjected to reduced neuronal activity by blockade of immature GABAA receptors. These results suggest that DCX supports developing dendrites, in addition to its role in neuronal migration.
Microtubule-Associated Protein 1B Interaction with Tubulin Tyrosine Ligase Contributes to the Control of Microtubule Tyrosination
Authors: Utreras Elías , Jiménez-Mateos Eva Maria , Contreras-Vallejos Erick , Tortosa Elena , Pérez Mar , Rojas Sebastián , Saragoni Lorena , Maccioni Ricardo B. , Avila Jesús , González-Billault Christian
Published: December 2007

Microtubule-associated protein 1B (MAP1B) is the first microtubule-associated protein to be expressed during nervous system development. MAP1B belongs to a large family of proteins that contribute to the stabilization and/or enhancement of microtubule polymerization. These functions are related to the control of the dynamic properties of microtubules. The C-terminal domain of the neuronal α-tubulin isotype is characterized by the presence of an acidic polypeptide, with the last amino acid being tyrosine. This tyrosine residue may be enzymatically removed from the protein by an unknown carboxypeptidase activity. Subsequently, the tyrosine residue is again incorporated into this tubulinby another enzyme, tubulin tyrosine ligase, to yield tyrosinated tubulin. Because neurons lacking MAP1B have a reduced proportion of tyrosinated microtubules, we analyzed the possible interaction between MAP1B and tubulin tyrosine ligase. Our results show that these proteins indeed interact and that the interaction is not affected by MAP1B phosphorylation. Additionally, neurons lacking MAP1B, when exposed to drugs that reversibly depolymerize microtubules, do not fully recover tyrosinated microtubules upon drug removal. These results suggest that MAP1B regulates tyrosination of α-tubulin in neuronal microtubules. This regulation may be important for general processes involved in nervous system development such as axonal guidance and neuronal migration.
Exploring Cortical Subplate Evolution Using Magnetic Resonance Imaging of the Fetal Brain
Authors: Perkins L. , Hughes E. , Srinivasan L. , Allsop J. , Glover A. , Kumar S. , Fisk N. , Rutherford M.
Published: December 2007

The subplate is a transient structure essential for normal development of the cortex. We used magnetic resonance imaging of the fetal brain to assess cortical subplate evolution between 20 and 35 weeks gestation. Two-dimensional measures of diameter were obtained for the cortex, subplate and fetal white matter. The subplate was originally seen as a continuous band at early gestations measuring up to 4.5 mm. It became magnetic resonance invisible from approximately 28 weeks initially from the depths of the sulci and then from the tops of the gyri. The disappearance of the subplate was regional, involuting most rapidly in the parietal lobe and remaining prominent in the anterior temporal lobe up to 35 weeks.
Natalizumab: Targeting α4-Integrins in Multiple Sclerosis
Authors: Engelhardt Britta , Kappos Ludwig
Published: December 2007

In 1992, it was shown that monoclonal antibodies blocking α4-integrins prevent the development of experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis (MS). As α4β1-integrin was demonstrated to mediate the attachment of immune-competent cells to inflamed brain endothelium in experimental autoimmune encephalomyelitis, the therapeutic effect was attributed to the inhibition of immune cell extravasation and inflammation in the central nervous system. This novel therapeutic approach was rapidly and successfully translated into the clinic. The humanized anti-α4-integrin antibody natalizumab demonstrated an unequivocal therapeutic effect in preventing relapses and slowing down the pace of neurological deterioration in patients with relapsing-remitting MS in phase II and phase III clinical trials. The occurrence of 3 cases of progressive multifocal leukoencephalopathy in patients treated with natalizumab led to the voluntary withdrawal of the drug from the market. After a thorough safety evaluation of all patients receiving this drug in past and ongoing studies for MS and Crohn’s disease, natalizumab again obtained approval in the US and the European Community. A treatment targeting leukocyte trafficking in MS has now re-entered the clinic. Further thorough evaluation is necessary for a better understanding of the risk-benefit balance of this new treatment option for relapsing MS. In this review, we discuss the basic mechanism of action, key clinical results of clinical trials and the emerging indication of natalizumab in MS.
Humanized Anti-CD25 Antibody Treatment with Daclizumab in Multiple Sclerosis
Authors: Martin Roland
Published: December 2007

Monoclonal antibodies against a variety of receptors and molecules are currently being introduced in clinical medicine. One of these targets is the interleukin-2 receptor α-chain CD25. The humanized monoclonal anti-CD25 antibody daclizumab (Zenapax®) has been approved several years ago for the prevention of allotransplant rejection and adult T cell leukemia. Following promising observations in uveitis, daclizumab has been tested in a number of small clinical trials in multiple sclerosis based on the rationale that blocking CD25 would prevent the expansion of autoreactive T lymphocytes. The data from this preliminary clinical exploration as well as findings about the mechanism of action of anti-CD25 treatment are summarized in this study.
Preclinical Assessment of Therapeutic Antibodies against Human CD40 and Human Interleukin-12/23p40 in a Nonhuman Primate Model of Multiple Sclerosis
Authors: ’t Hart Bert A. , Hintzen Rogier Q. , Laman Jon D.
Published: December 2007

Background: Proinflammatory cytokines, such as interleukin (IL)-12 and IL-23, and costimulatory molecules on antigen-presenting cells (APC), such as CD40, are critical to autoreactive T cell activation by APC, and hence, are considered relevant targets of therapy for immune-mediated inflammatory diseases (IMID). Objective: The current review discusses the preclinical evaluation of two novel immunotherapeutic monoclonal antibodies (mAbs), one directed against human IL-12/23p40 and the other against CD40. As the antibodies only recognize their target molecule in primates, the efficacy could not be tested in rodent models. Results: As a preclinical IMID model for the in vivo evaluation of both mAbs, we have used the experimental autoimmune/allergic encephalomyelitis (EAE) model in common marmoset monkeys (Callithrix jacchus). Both mAbs show beneficial activities in the EAE model when administered early in disease development as well as after the onset of brain inflammation. The treatment effects were evaluated using a combination of quantitative magnetic resonance imaging and a series of ex vivo and immunopathological evaluations. Conclusion: The promising effects during ongoing disease in a relevant preclinical IMID model illustrate the potential of these two antibodies as treatment of IMID, in particular for multiple sclerosis on which disease EAE has been modeled.
Molecular Determinants of Bat Wing Development
Authors: Sears K.E.
Published: December 2007

The specialization of the forelimb into a wing allowed bats to become the only mammals to achieve powered flight. Recent studies in developmental biology have begun to elucidate the molecular mechanisms behind elements of this important morphological transformation. Specifically, researchers have identified molecular changes contributing to: the formation of the bat wing membrane, the elongation of skeletal elements of the bat wing and the reduction of the bat ulna. The general picture emerging from this research is that small changes in the expression of genes critical to many aspects of development have driven large changes in bat wing morphology. Thus, bats can be added to the growing list of groups in which expression changes in key developmental genes have been linked to the evolution of morphological innovations (e.g. early bilaterians, cetaceans, insects).
Morphogenesis in Bat Wings: Linking Development, Evolution and Ecology
Authors: Adams Rick A.
Published: December 2007

The evolution of powered flight in mammals required specific developmental shifts from an ancestral limb morphology to one adapted for flight. Through studies of comparative morphogenesis, investigators have quantified points and rates of divergence providing important insights into how wings evolved in mammals. Herein I compare growth, development and skeletogenesis of forelimbs between bats and the more ancestral state provided by the rat (Rattus norvegicus) and quantify growth trajectories that illustrate morphological divergence both developmentally and evolutionarily. In addition, I discuss how wing shape is controlled during morphogenesis by applying multivariate analyses of wing bones and wing membranes and discuss how flight dynamics are stabilized during flight ontogeny. Further, I discuss the development of flight in bats in relation to the ontogenetic niche and how juveniles effect populational foraging patterns. In addition, I provide a hypothetical ontogenetic landscape model that predicts how and when selection is most intense during juvenile morphogenesis and test this model with data from a population of the little brown bat, Myotis lucifugus.
Growth and Development of Two Species of Bats in a Shared Maternity Roost
Authors: Hermanson John W. , Wilkins Kenneth T.
Published: December 2007

Skeletogenesis was studied in two species of bats, Myotis austroriparius (southeastern brown bat) and Tadarida brasiliensis (Brazilian free-tailed bat), occupying a maternity roost in central Florida. These bats often use distinct maternity roost environments, so this provided an opportunity to examine differential patterns of long bone growth while fetuses and newborn developed under similar environmental conditions. Some differences in the timing of onset of osteogenesis were revealed in the bats, indicating that some elements of the hindlimb develop relatively more rapidly in T. brasiliensis than in M. austroriparius. Some variance was also noted, with similarity to other species previously studied by others, in the exact timing and elongation of both long bones, as well as carpal and tarsal bones. In contrast to many elements of the long appendicular skeleton of developing Mus musculus, the bats all exhibit relatively precocial patterns of osteogenesis during which cartilaginous precursors are replaced by bone tissue. The relative advanced timing of osteogenesis in select hindlimb bones of T. brasiliensis may account for its relatively low neonatal mortality compared to M. austroriparius newborn in the same roost.
Forelimb versus Hindlimb Skeletal Development in the Big Brown Bat, Eptesicus fuscus: Functional Divergence Is Reflected in Chondrocytic Performance in Autopodial Growth Plates
Authors: Farnum Cornelia E. , Tinsley Michelle , Hermanson John W.
Published: December 2007

The morphology of the chiropteran forelimb demonstrates musculoskeletal specializations for powered flight essentially unique among mammals, including extreme elongation of the distal skeletal elements. Recent studies have focused primarily on the relative timing and levels of gene expression during early stages of endochondral ossification in the chiropteran embryo for clues to the molecular basis of the evolutionary origins of flight in these species. The goal of the current study was to examine how elongation of skeletal elements of the forelimb autopod is achieved through a combination of cellular proliferation, cellular enlargement and matrix synthesis during a period of rapid postnatal growth in Eptesicus fuscus. Quantitative analyses were done of multiple performance parameters of growth plate chondrocytes during all phases of the differentiation cascade. Fourteen autopodial growth plates from the forelimb and hindlimb of one individual, as well as the proximal tibial growth plate, were collected and analyzed. Significant differences were seen in all performance parameters examined. Particularly striking were the differences between growth plates of the manus and pes in the size of the pool of chondrocytes in all cellular zones and rates of turnover of terminal cells. The magnitude of hypertrophy of chondrocytes in growth plates of the manus in E. fuscus far exceeded what has been reported previously in any species, even in rapidly elongating rodent long bones. Volume changes approaching ×70 and height changes of 50–60 µm/cell (paralleling the direction of growth) occurred after proliferation in the most rapidly growing growth plates. The data demonstrate that final differences in lengths of homologous skeletal elements in the autopod of the forelimb and hindlimb of this species result not just from an initiating factor early in development, but from continued quantitative differences in chondrocytic performance during postnatal bone elongation as measured by multiple kinetic-based parameters.
Postnatal Bone Elongation of the Manus versus Pes: Analysis of the Chondrocytic Differentiation Cascade in Mus musculus and Eptesicus fuscus
Authors: Farnum Cornelia E. , Tinsley Michelle , Hermanson John W.
Published: December 2007

Bones elongate postnatally by endochondral ossification as cells of the cartilaginous growth plate undergo a differentiation cascade of proliferation, cellular hypertrophy and matrix synthesis. Interspecific comparisons of homologous bones elongating at different rates has been a useful approach for studying the dynamics of this process. The purpose of this study was to measure quantitative stereological parameters of growth plates of the third digit of the manus and pes of the laboratory mouse, and make comparisons to chondrocytic performance parameters in the homologous bones of the big brown bat, Eptesicus fuscus, where extremely rapid postnatal elongation of bones of the manus is associated with skeletal modifications for powered flight. Measurements were made across all zones of forelimb and hindlimb autopod growth plates by dividing each growth plate into strata of equal height (from thirteen 200-µm-high strata in the metacarpus to five 40-µm-high strata in phalangeal bones of the pes). Results indicate that all chondrocytic performance parameters known to quantitatively contribute to the elongation potential of a growth plate change together. A significant finding was that in growth plates of the chiropteran manus, final hypertrophic cell size and shape were achieved early in the zone of hypertrophy, indicating that interstitial expansion of the growth plate resulting from the incremental chondrocytic height increase in the direction of elongation was completed soon after the transition from the cessation of proliferation to the initiation of hypertrophy. This is unlike what has been reported in most mammalian growth plates previously analyzed, but is the situation in the proximal tibial growth plate of rapidly growing frogs and precocial birds. This suggests that a similar adaptation for stabilization of a rapidly elongating bone has evolved independently in three widely separated groups that have in common rapid growth in limbs to be used for early active, powered locomotion.
Associations between Notch-2, Akt-1 and HER2/neu Expression in Invasive Human Breast Cancer: A Tissue Microarray Immunophenotypic Analysis on 98 Patients
Authors: Florena Ada Maria , Tripodo Claudio , Guarnotta Carla , Ingrao Sabrina , Porcasi Rossana , Martorana Anna , Lo Bosco Giosuè , Cabibi Daniela , Franco Vito
Published: December 2007

Objective: We aimed to investigate the existence of associations between well-established and newly recognized biological and phenotypic features of breast cancer involved in tumor progression and prognosis. Methods: Ninety-eight cases of invasive breast cancer were assessed for the immunohistochemical expression of estrogen and progesterone receptors, Ki-67, HER2, Akt-1, and Notch-2, using the tissue microarray technique. Data regarding tumor histotype, histological grade, tumor size and lymph node status were collected for each patient and included in the analysis. Results: Several significant associations between histological and/or immunophenotypic features came from the analysis of our data. Positive associations were observed between estrogen and progesterone receptors, tumor grade and proliferation index, tumor grade and HER2, Akt-1 and estrogen receptors, and Notch-2 and HER2. Inverse associations were noted between hormone receptors and tumor grade, hormone receptors and HER2, Akt-1 and tumor grade, and Akt-1 and nodal invasion. Conclusions: Our results, showing the existence of a number of estrogen receptor-positive tumors with Akt-1 expression, better degree of differentiation, and no lymph node involvement, along with the presence of HER2-positive tumors with strong Notch-2 expression, support the role of Notch and Akt in breast cancer progression and suggest that they may also represent new appealing therapeutic targets.
The Lymphatic Infiltration Identified by D2-40 Monoclonal Antibody Predicts Lymph Node Metastasis in Submucosal Invasive Colorectal Cancer
Authors: Kawaura Ken , Fujii Satoshi , Murata Yukinori , Hasebe Takahiro , Ishii Genichiro , Itoh Tohru , Sano Yasushi , Saito Norio , Ochiai Atsushi
Published: December 2007

Background and Study Aims: Lymphatic infiltration has been recognized as a significant risk factor for lymph node metastasis of submucosal invasive colorectal cancer (SICC), but it is difficult to detect microscopically on hematoxylin and eosin (H&E)-stained slides. We therefore identified lymphatic infiltration of tumor cells with D2-40 monoclonal antibody, which reacts specifically against the endothelium of lymphatic vessels, to make an objective and precise diagnosis. Patients and Methods: The surgical specimens of 122 consecutive patients with nonpedunculated SICC were examined for lymphatic infiltration by immunohistochemical staining with D2-40 monoclonal antibody (LI-D) and for venous infiltration by Elastica van Gieson staining (VI-E). Results: Lymph node metastasis was found in 20 patients. Multivariate analysis showed that LI-D (p = 0.0415) and VI-E (p = 0.0119) were significant risk factors for lymph node metastasis. Regardless of the presence of risk factors including at least either lymphatic infiltration or venous infiltration, no lymph node metastasis-positive patients were found (0%) among the 25 patients whose colorectal cancer had a submucosal invasive depth of less than 1,500 µm. No lymph node metastasis was found in any of the patients with a depth of submucosal invasion of less than 3,000 µm, who had no risk factors, including LI-D or VI-E. Conclusions: Correct evaluation of lymphatic infiltration by immunohistochemical staining with D2-40 monoclonal antibody may play a crucial role in determining whether there are indications for additional treatment in the management of endoscopically resected SICC.