bluuebunny/crossref_metadata_2025_split huggingface dataset:
The lefty-related factor Xatv acts as a feedback inhibitor of Nodal signaling in mesoderm induction and L-R axis development in Xenopus
Authors: Cheng Abby M. S. , Thisse Bernard , Thisse Christine , Wright Christopher V. E. 
Published: April 2021

ABSTRACT
In mouse, lefty genes play critical roles in the left-right (L-R) axis determination pathway. Here, we characterize the Xenopus lefty-related factor antivin (Xatv). Xatv expression is first observed in the marginal zone early during gastrulation, later becoming restricted to axial tissues. During tailbud stages, axial expression resolves to the neural tube floorplate, hypochord, and (transiently) the notochord anlage, and is joined by dynamic expression in the left lateral plate mesoderm (LPM) and left dorsal endoderm.
An emerging paradigm in embryonic patterning is that secreted antagonists regulate the activity of intercellular signaling factors, thereby modulating cell fate specification. Xatv expression is rapidly induced by dorsoanterior-type mesoderm inducers such as activin or Xnr2. Xatv is not an inducer itself, but antagonizes both Xnr2 and activin. Together with its expression pattern, this suggests that Xatv functions during gastrulation in a negative feedback loop with Xnrs to affect the amount and/or character of mesoderm induced. Our data also provide insights into the way that lefty/nodal signals interact in the initiation of differential L-R morphogenesis. Right-sided misexpression of Xnr1 (endogenously expressed in the left LPM) induces bilateral Xatv expression. Left-sided Xatv overexpression suppresses Xnr1/XPitx2 expression in the left LPM, and leads to severely disturbed visceral asymmetry, suggesting that active ‘left’ signals are critical for L-R axis determination in frog embryos. We propose that the induction of lefty/Xatv in the left LPM by nodal/Xnr1 provides an efficient self-regulating mechanism to downregulate nodal/Xnr1 expression and ensure a transient ‘left’ signal within the embryo.
Control of chick tectum territory along dorsoventral axis by Sonic hedgehog
Authors: Watanabe Yuji , Nakamura Harukazu 
Published: April 2021

ABSTRACT
Chick midbrain comprises two major components along the dorsoventral axis, the tectum and the tegmentum. The alar plate differentiates into the optic tectum, while the basal plate gives rise to the tegmentum. It is largely unknown how the differences between these two structures are molecularly controlled during the midbrain development. The secreted protein Sonic hedgehog (Shh) produced in the notochord and floor plate induces differentiation of ventral cell types of the central nervous system. To evaluate the role of Shh in the establishment of dorsoventral polarity in the developing midbrain, we have ectopically expressed Shh unilaterally in the brain vesicles including whole midbrain of E1.5 chick embryos in ovo. Ectopic Shh repressed normal growth of the tectum, producing dorsally enlarged tegmentum region. In addition, the expression of several genes crucial for tectum formation was strongly suppressed in the midbrain and isthmus. Markers for midbrain roof plate were inhibited, indicating that the roof plate was not fully generated. After E5, the tectum territory of Shh-transfected side was significantly reduced and was fused with that of untransfected side. Moreover, ectopic Shh induced a considerable number of SC1-positive motor neurons, overlapping markers such as HNF-3β (floor plate), Isl-1 (postmitotic motor neuron) and Lim1/2. Dopaminergic and serotonergic neurons were also generated in the dorsally extended region. These changes indicate that ectopic Shh changed the fate of the mesencephalic alar plate to that of the basal plate, suppressing the massive cell proliferation that normally occurs in the developing tectum. Taken together our results suggest that Shh signaling restricts the tectum territory by controlling the molecular cascade for tectum formation along dorsoventral axis and by regulating neuronal cell diversity in the ventral midbrain.
Large-scale cDNA analysis reveals phased gene expression patterns during preimplantation mouse development
Authors: Ko Minoru S. H. , Kitchen John R. , Wang Xiaohong , Threat Tracy A. , Wang Xueqian , Hasegawa Aki , Sun Tong , Grahovac Marija J. , Kargul George J. , Lim Meng K. , Cui YuShun , Sano Yuri , Tanaka Tetsuya , Liang Yuling , Mason Scott , Paonessa Paul D. , Sauls Althea D. , DePalma Grace E. , Sharara Rana , Rowe Lucy B. , Eppig Janan , Morrell Chris , Doi Hirofumi 
Published: April 2021

ABSTRACT
Little is known about gene action in the preimplantation events that initiate mammalian development. Based on cDNA collections made from each stage from egg to blastocyst, 25438 3′-ESTs were derived, and represent 9718 genes, half of them novel. Thus, a considerable fraction of mammalian genes is dedicated to embryonic expression. This study reveals profound changes in gene expression that include the transient induction of transcripts at each stage. These results raise the possibility that development is driven by the action of a series of stage-specific expressed genes. The new genes, 798 of them placed on the mouse genetic map, provide entry points for analyses of human and mouse developmental disorders.
Specification of neuropeptide Y phenotype in visual cortical neurons by leukemia inhibitory factor
Authors: Wahle Petra , Gorba Thorsten , Wirth Marcus J. , Obst-Pernberg Kirstin 
Published: April 2021

ABSTRACT
Building the complex mammalian neocortex requires appropriate numbers of neurochemically specified neurons. It is not clear how the highly diverse cortical interneurons acquire their distinctive phenotypes. The lack of genetic determination implicates environmental factors in this selection and specification process. We analysed, in organotypic visual cortex cultures, the specification of neurons expressing neuropeptide Y (NPY), a potent anticonvulsant. Endogenous brain-derived neurotrophic factor and neurotrophin 4/5 play no role in early NPY phenotype specification. Rather, the decision to express NPY is made during a period of molecular plasticity during which differentiating neurons with the potential to express NPY compete for the cytokine leukemia inhibitory factor which is produced in the cortex, but is negatively regulated by thalamic afferences. The neurons that fail in this competition are parvalbuminergic basket and chandelier neurons, which express NPY transiently, but will not acquire a permanent NPY expression. They switch into a facultative NPY expression mode, and remain responsive to the neurotrophins which modulate NPY expression later in development.
BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation
Authors: Minina Eleonora , Wenzel Hans Markus , Kreschel Conny , Karp Seth , Gaffield William , McMahon Andrew P. , Vortkamp Andrea 
Published: April 2021

During endochondral ossification, two secreted signals, Indian hedgehog (Ihh) and parathyroid hormone-related protein (PTHrP), have been shown to form a negative feedback loop regulating the onset of hypertrophic differentiation of chondrocytes. Bone morphogenetic proteins (BMPs), another family of secreted factors regulating bone formation, have been implicated as potential interactors of the Ihh/PTHrP feedback loop. To analyze the relationship between the two signaling pathways, we used an organ culture system for limb explants of mouse and chick embryos. We manipulated chondrocyte differentiation by supplementing these cultures either with BMP2, PTHrP and Sonic hedgehog as activators or with Noggin and cyclopamine as inhibitors of the BMP and Ihh/PTHrP signaling systems. Overexpression of Ihh in the cartilage elements of transgenic mice results in an upregulation of PTHrP expression and a delayed onset of hypertrophic differentiation. Noggin treatment of limbs from these mice did not antagonize the effects of Ihh overexpression. Conversely, the promotion of chondrocyte maturation induced by cyclopamine, which blocks Ihh signaling, could not be rescued with BMP2. Thus BMP signaling does not act as a secondary signal of Ihh to induce PTHrP expression or to delay the onset of hypertrophic differentiation. Similar results were obtained using cultures of chick limbs.We further investigated the role of BMP signaling in regulating proliferation and hypertrophic differentiation of chondrocytes and identified three functions of BMP signaling in this process. First we found that maintaining a normal proliferation rate requires BMP and Ihh signaling acting in parallel. We further identified a role for BMP signaling in modulating the expression of Ihh. Finally, the application of Noggin to mouse limb explants resulted in advanced differentiation of terminally hypertrophic cells, implicating BMP signaling in delaying the process of hypertrophic differentiation itself. This role of BMP signaling is independent of the Ihh/PTHrP pathway.
Sonic hedgehog is a survival factor for hypaxial muscles during mouse development
Authors: Krüger Marcus , Mennerich Detlev , Fees Stefan , Schäfer Ralf , Mundlos Stefan , Braun Thomas 
Published: April 2021

ABSTRACT
Sonic hedgehog (Shh) has been proposed to function as an inductive and trophic signal that controls development of epaxial musculature in vertebrate embryos. In contrast, development of hypaxial muscles was assumed to occur independently of Shh. We here show that formation of limb muscles was severely affected in two different mouse strains with inactivating mutations of the Shh gene. The limb muscle defect became apparent relatively late and initial stages of hypaxial muscle development were unaffected or only slightly delayed. Micromass cultures and cultures of tissue fragments derived from limbs under different conditions with or without the overlaying ectoderm indicated that Shh is required for the maintenance of the expression of myogenic regulatory factors (MRFs) and, consecutively, for the formation of differentiated limb muscle myotubes. We propose that Shh acts as a survival and proliferation factor for myogenic precursor cells during hypaxial muscle development. Detection of a reduced but significant level of Myf5 expression in the epaxial compartment of somites of Shh homozygous mutant embryos at E9.5 indicated that Shh might be dispensable for the initiation of myogenesis both in hypaxial and epaxial muscles. Our data suggest that Shh acts similarly in both somitic compartments as a survival and proliferation factor and not as a primary inducer of myogenesis.
Activation of rabbit oocytes: the impact of the Ca2+ signal regime on development
Authors: Ozil Jean-Pierre , Huneau Daniel 
Published: April 2021

ABSTRACT
Postfertilization manipulation of mammalian embryos results in various developmental alterations. To determine whether the manipulation of the Ca2+ regime causing oocyte activation is a valuable experimental means in helping understand the biological process by which embryos integrate signals from outside and later regulate gene expression, we linked Ca2+ signal parameters i.e. amplitude, number and frequency, with the efficiency and quality of postimplantation development. Freshly ovulated rabbit oocytes were subjected to repetitive and modulated Ca2+ influx. The results provide three major pieces of information. Firstly, the Ca2+ stimulus is the most efficient signal activating mammalian eggs when it is applied in a repetitive manner, the amplitude being the crucial factor.
Secondly, the dynamics of early cleavage does not appear to be determined by either the frequency or the amplitude of modulation of the Ca2+ signal that activates the oocyte. Thirdly, amplitude and temporal modulation of the Ca2+ signal in the early minutes influences the developmental performance and the morphology of the rabbit parthenogenetic conceptus at day 11.5 of pregnancy. The results demonstrate the importance of epigenetic events during postfertilization as well as the possible uses of Ca2+ modulation in studying long term developmental effects.
GAP-43 promoter elements in transgenic zebrafish reveal a difference in signals for axon growth during CNS development and regeneration
Authors: Udvadia Ava J. , Köster Reinhard W. , Skene J. H. Pate 
Published: April 2021

ABSTRACT
A pivotal event in neural development is the point at which differentiating neurons become competent to extend long axons. Initiation of axon growth is equally critical for regeneration. Yet we have a limited understanding of the signaling pathways that regulate the capacity for axon growth during either development or regeneration. Expression of a number of genes encoding growth associated proteins (GAPs) accompanies both developmental and regenerative axon growth and has led to the suggestion that the same signaling pathways regulate both modes of axon growth. We have tested this possibility by asking whether a promoter fragment from a well characterized GAP gene, GAP-43, is sufficient to activate expression in both developing and regenerating neurons. We generated stable lines of transgenic zebrafish that express green fluorescent protein (GFP) under regulation of a 1 kb fragment of the rat GAP-43 gene, a fragment that contains a number of evolutionarily conserved elements. Analysis of GFP expression in these lines confirms that the rat 1 kb region can direct growth-associated expression of the transgene in differentiating neurons that extend long axons. Furthermore, this region supports developmental down-regulation of transgene expression which, like the endogenous gene, coincides with neuronal maturation. Strikingly, these same sequences are insufficient for directing expression in regenerating neurons. This finding suggests that signaling pathways regulating axon growth during development and regeneration are not the same. While these results do not exclude the possibility that pathways involved in developmental axon growth are also active in regenerative growth, they do indicate that signaling pathway(s) controlling activation of the GAP-43 gene after CNS injury differ in at least one key component from the signals controlling essential features of developmental axon growth.
The AP-2 transcription factor is required for joint formation and cell survival in Drosophila leg development
Authors: Kerber Birgit , Monge Ignacio , Mueller Martin , Mitchell Pamela J. , Cohen Stephen M. 
Published: April 2021

ABSTRACT
Flies mutant for the Drosophila homologue of the mammalian transcription factor AP-2 show a severe reduction in leg length and fail to develop joint structures. Presumptive joint cells express dAP-2 in response to Notch signaling. dAP-2 is required for joint cell differentiation and can induce formation of supernumerary joints when misexpressed. Although dAP-2 is expressed only in presumptive joint cells, its activity is required to support cell survival in the entire leg segment. Taken together, our data indicate that dAP-2 is an important mediator of Notch activity in leg development.
Mesodermal patterning defect in mice lacking the Ste20 NCK interacting kinase (NIK)
Authors: Xue Yingzi , Wang Xiaozhong , Li Zhai , Gotoh Noriko , Chapman Deborah , Skolnik Edward Y. 
Published: April 2021

ABSTRACTWe have previously shown that the Drosophila Ste20 kinase encoded by misshapen (msn) is an essential gene in Drosophila development. msn function is required to activate the Drosophila c-Jun N-terminal kinase (JNK), basket (Bsk), to promote dorsal closure of the Drosophila embryo. Later in development, msn expression is required in photoreceptors in order for their axons to project normally. A mammalian homolog of msn, the NCK-interacting kinase (NIK) (recently renamed to mitogen-activated protein kinase kinase kinase kinase 4; Map4k4), has been shown to activate JNK and to bind the SH3 domains of the SH2/SH3 adapter NCK. To determine whether NIK also plays an essential role in mammalian development, we created mice deficient in NIK by homologous recombination at the Nik gene. Nik−/− mice die postgastrulation between embryonic day (E) 9.5 and E10.5. The most striking phenotype in Nik−/− embryos is the failure of mesodermal and endodermal cells that arise from the anterior end of the primitive streak (PS) to migrate to their correct location. As a result Nik−/− embryos fail to develop somites or a hindgut and are truncated posteriorly. Interestingly, chimeric analysis demonstrated that NIK has a cell nonautonomous function in stimulating migration of presomitic mesodermal cells away from the PS and a second cell autonomous function in stimulating the differentiation of presomitic mesoderm into dermomyotome. These findings indicate that despite the large number of Ste20 kinases in mammalian cells, members of this family play essential nonredundant function in regulating specific signaling pathways. In addition, these studies provide evidence that the signaling pathways regulated by these kinases are diverse and not limited to the activation of JNK because mesodermal and somite development are not perturbed in JNK1-, and JNK2-deficient mice.
Molecular and functional evidence for early divergence of an endothelin-like system during metazoan evolution: analysis of the Cnidarian, hydra
Authors: Zhang Jinsong , Leontovich Alexey , Sarras Michael P. 
Published: April 2021

ABSTRACT
A novel putative endothelin-converting enzyme (ECE) has been cloned from hydra, a freshwater invertebrate that belongs to the second oldest phylum of the animal kingdom. As an integral component of the endothelin system, vertebrate ECE functions in the activation of endothelin (ET) peptides. Vertebrate ETs are (1) the most potent vasoconstrictors known in mammals; and (2) function as essential signaling ligands during development of tissues derived from neural crest cells. To date, only a limited number of immunocytochemical studies have suggested the presence of endothelin-like peptides in invertebrates. Based on structural and functional analyses, we present evidence for a functional endothelin-like system in hydra that is involved in both muscle contraction and developmental processes. These findings indicate the broad use of endothelin systems in metazoans and also indicate that this type of signaling system arose early in evolution even before divergence of protostomes and deuterostomes.
The transcription factor Schnurri plays a dual role in mediating Dpp signaling during embryogenesis
Authors: Torres-Vazquez Jesus , Park Sangbin , Warrior Rahul , Arora Kavita 
Published: April 2021

ABSTRACTDecapentaplegic (Dpp), a homolog of vertebrate bone morphogenic protein 2/4, is crucial for embryonic patterning and cell fate specification in Drosophila. Dpp signaling triggers nuclear accumulation of the Smads Mad and Medea, which affect gene expression through two distinct mechanisms: direct activation of target genes and relief of repression by the nuclear protein Brinker (Brk). The zinc-finger transcription factor Schnurri (Shn) has been implicated as a co-factor for Mad, based on its DNA-binding ability and evidence of signaling dependent interactions between the two proteins. A key question is whether Shn contributes to both repression of brk as well as to activation of target genes. We find that during embryogenesis, brk expression is derepressed in shn mutants. However, while Mad is essential for Dpp-mediated repression of brk, the requirement for shn is stage specific. Analysis of brk; shn double mutants reveals that upregulation of brk does not account for all aspects of the shn mutant phenotype. Several Dpp target genes are expressed at intermediate levels in double mutant embryos, demonstrating that shn also provides a brk-independent positive input to gene activation. We find that Shn-mediated relief of brk repression establishes broad domains of gene activation, while the brk-independent input from Shn is crucial for defining the precise limits and levels of Dpp target gene expression in the embryo.
Immunohistological studies on the reconstitution of nephric tubules from dissociated cells
Authors: Okada T. S. 
Published: April 2021

ABSTRACT
Dissociated cells of metanephri of 16-day chick embryos were reaggregated immediately or several days after culturing at a glass-medium interface to encourage spreading. The reaggregates were organ-cultured at the air-medium interface on nutrient agar for up to 4 days. They were examined immunohistologically using fluorescein conjugated antiserum-globulin directed against semi-purified ‘kidney-specific’ antigens. The specific antigens (‘K-antigens’) are localized only in the secretory tubules of kidney, and the conjugated antiserum stains only the cells originating from this particular tissue. In the reaggregates of fresh suspension, sorting out of the positive and negative cells started after 1 day in organ culture and the sorting out and selective localization were essentially completed after 4 days. Almost all of the positive cells were incorporated in the reconstituted tubular structures within the reaggregates, while the outer wall of the reaggregates consisted of fluorescence negative epithelial tissue. In the reaggregates of 30 hr. monolayer culture localization was somewhat less selective: Epithelial cells with positive fluorescence very often formed patches of epithelial tissue in the outer wall. Reconstitution of tubular structures hardly occurred in reaggregates after 96 hr. in monolayer. Almost all of the cells of the organ-cultured reaggregates were negative cells. The results indicate that fluorescent antibody technique can be a potent tool for identifying cells derived from a single tissue. The gradual loss of the histoformative capacity in monolayer culture was discussed in relation to the antigenic changes of the cells occurring in such culture conditions.
Genes and genotypes affecting the teeth of the mouse
Authors: Grüneberg Hans 
Published: April 2021

ABSTRACT
This paper is dedicated in gratitude and affection to Professor Hans Nachtsheim on the occasion of his seventy-fifth birthday (13th June 1965).
The teeth of mammals have been studied in great detail both by palaeontologists and by taxonomists who are interested in differences between species or higher systematic categories which are ultimately genetic in nature. By contrast, little is known about intra-specific genetic variability of the dentition. An invitation to participate in an ‘Institute for Advanced Education in Dental Research’ sponsored by the American College of Dentists provided an occasion to explore the situation in the laboratory and, presently, in the wild house mouse. The main results of this search are given in this paper. The extent of the intra-specific variance discovered may help systematists in assessing how much importance to attach to the differences they encounter; and it will be shown how easily one can be misled, in a limited sample, as to what is ‘normal’. Two characteristic dental syndromes to be described pose a new kind of problem to dental pathology. The fact that their interpretation in developmental terms is far from obvious may act as a stimulus to further work on the embryology of both the dental crown and the roots. The material to be described in this paper offers opportunities for such an approach not hitherto available.
Submicroscopical observations on the differentiation of chick gonads
Authors: Narbaitz Roberto , Adler Ruben 
Published: April 2021

ABSTRACT
The role of hormones in gonadal differentiation has not been fully elucidated. One of the main problems consists in determining the exact moment in which steroid synthesis begins. If, as has been claimed, sex hormones act as organizers and are responsible for the morphological changes which characterize gonadal differentiation, then they should appear before these changes take place.