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PubMed2000

The adhesion signaling molecule p190 RhoGAP is required for morphogenetic processes in neural development.

Rho GTPases direct actin rearrangements in response to a variety of extracellular signals. P190 RhoGAP (GTPase activating protein) is a potent Rho regulator that mediates integrin-dependent adhesion signaling in cultured cells. We have determined that p190 RhoGAP is specifically expressed at high levels throughout the developing nervous system. Mice lacking functional p190 RhoGAP exhibit several defects in neural development that are reminiscent of those described in mice lacking certain mediators of neural cell adhesion. The defects reflect aberrant tissue morphogenesis and include abnormalities in forebrain hemisphere fusion, ventricle shape, optic cup formation, neural tube closure, and layering of the cerebral cortex. In cells of the neural tube floor plate of p190 RhoGAP mutant mice, polymerized actin accumulates excessively, suggesting a role for p190 RhoGAP in the regulation of +Rho-mediated actin assembly within the neuroepithelium. Significantly, several of the observed tissue fusion defects seen in the mutant mice are also found in mice lacking MARCKS, the major substrate of protein kinase C (PKC), and we have found that p190 RhoGAP is also a PKC substrate in vivo. Upon either direct activation of PKC or in response to integrin engagement, p190 RhoGAP is rapidly translocated to regions of membrane ruffling, where it colocalizes with polymerized actin. Together, these results suggest that upon activation of neural adhesion molecules, the action of PKC and p190 RhoGAP leads to a modulation of Rho GTPase activity to direct several actin-dependent morphogenetic processes required for normal neural development.

Alleles↗

PubMed2004

Comprehensive genomics linking between neural development and cancer: neuroblastoma as a model.

Cancer cells are derived from their precursor cells, which normally develop to the matured cells to form individual organs. Neuroblastoma, one of the most common pediatric solid tumors, originates from possible cancer stem cells derived from the neural crest. During the development, neural crest cells segregate into several lineages such as sensory, enteric and sympathetic neurons. However, the genetic events to cause neuroblastoma occur only in the sympathetic precursor cells or cancer stem cells. Furthermore, spontaneous regression of a subset of neuroblastoma found in patients under one year of age mimics a developmentally programmed neuronal cell death that occurs in normal sympathetic neurons during the perinatal period. Thus, the genetic events to cause neuroblastoma may be programmed to occur in a lineage-specific as well as developmentally regulated manner. In this review, we discuss about the molecular link between neural development and the genesis of neuroblastoma based on our comprehensive genomics approach.

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PubMed1995

Regulation of mammalian neural development by helix-loop-helix transcription factors.

Understanding of the molecular mechanisms of mammalian neural development has been greatly advanced by identification and characterization of the molecules homologous to the factors regulating Drosophila neurogenesis, which provides a powerful model system. Studies of Drosophila show that transcription factors with a helix-loop-helix (HLH) domain play an essential role in neurogenesis. Several lines of evidence demonstrate that mammalian homologues of the Drosophila HLH factors do also play an essential role in neural development. Mash-1, a mammalian HLH factor homologous to the products of Drosophila proneural genes achaete-scute complex, is a positive regulator of neurogenesis and required for differentiation of olfactory and autonomic neurons. In addition, HES-1, another mammalian HLH factor homologous to the products of Drosophila hairy and Enhancer of split, antagonizes the activity of Mash-1 and negatively regulates neurogenesis. Thus, positive and negative HLH factors interact with each other, and the balance between them is important for the developmental processes. Recent studies show that many other HLH factors exist expressed in the developing mammalian nervous system. In this article, the authors review mammalian HLH factors expressed in the nervous system and discuss the molecular aspect of mammalian neurogenesis.

Amino Acid Sequence↗

PubMed2003

Quantitative analysis of bristle number in Drosophila mutants identifies genes involved in neural development.

BACKGROUND: The identification of the function of all genes that contribute to specific biological processes and complex traits is one of the major challenges in the postgenomic era. One approach is to employ forward genetic screens in genetically tractable model organisms. In Drosophila melanogaster, P element-mediated insertional mutagenesis is a versatile tool for the dissection of molecular pathways, and there is an ongoing effort to tag every gene with a P element insertion. However, the vast majority of P element insertion lines are viable and fertile as homozygotes and do not exhibit obvious phenotypic defects, perhaps because of the tendency for P elements to insert 5' of transcription units. Quantitative genetic analysis of subtle effects of P element mutations that have been induced in an isogenic background may be a highly efficient method for functional genome annotation. RESULTS: Here, we have tested the efficacy of this strategy by assessing the extent to which screening for quantitative effects of P elements on sensory bristle number can identify genes affecting neural development. We find that such quantitative screens uncover an unusually large number of genes that are known to function in neural development, as well as genes with yet uncharacterized effects on neural development, and novel loci. CONCLUSIONS: Our findings establish the use of quantitative trait analysis for functional genome annotation through forward genetics. Similar analyses of quantitative effects of P element insertions will facilitate our understanding of the genes affecting many other complex traits in Drosophila.

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PubMed1989

Fetal neural development and schizophrenia.

The conference on Fetal Neural Development and Schizophrenia which was held in Washington, DC, May 31-June 1, 1988, focused on factors of possible etiological significance in fetal development. Schizophrenia researchers joined experts in brain imaging, neuropathological, and neurochemical changes in brain development and investigators of potential genetic and neurobehavioral causes of psychosis. The combined evidence suggested dysfunction in frontal and parieto-occipital neocortex, basal ganglia, hippocampus, and amygdala. Dopamine transmission was implicated both in basal ganglia deficits and in widespread neocortical disturbances. Viral infection, or excessive stress, during the second trimester of pregnancy, as well as obstetrical complications, minor physical anomalies, and brain defects, correlated positively with incidence of adult schizophrenia. Autonomic nonresponding, birth complications, and ventricular enlargement were found to be closely related to negative symptom schizophrenia in high-risk populations. A dual factor model of schizophrenia was suggested, where genetic and environmental influences combine to produce psychosis.

Brain↗

PubMed1997

Genetics of neural development in zebrafish.

Large-scale mutant screens in zebrafish have led to the identification of more than 50 genes affecting various aspects of neural development and function, including neural induction, anteroposterior and dorsoventral regionalization, axon pathfinding, neuronal differentiation and survival, and behavior. Phenotypic analysis of mutants for some of these genes has already uncovered important genetic and cellular interactions during development. Ongoing molecular analyses promise to further elucidate the mechanisms underlying neural development in vertebrates.

Animals↗

PubMed2003

The cadherin superfamily in neural development: diversity, function and interaction with other molecules.

Cell-cell interactions are crucial steps for the development of the highly complex nervous system. A variety of cell-cell adhesion molecules of the cadherin superfamily have been found to be expressed in the developing nervous system. Recently it was proposed classic cadherins are involved in various aspects of neural development such as regionalization, brain nucleus formation, neurite outgrowth, target recognition and synaptogenesis. Classic cadherins preferentially bind to the same cadherin subtype ("homophilic adhesion"), and this binding specificity can provide an "adhesive code" that can account for various aspects of neural morphogenesis. In addition, novel members of the cadherin superfamily are also involved in various steps of neural development. The function of these cadherins molecules is orchestrated in the cellular context by a complex network of signaling pathways such as the small GTPase pathway. Here, we will review the molecular properties of the cadherin superfamily and their coordinated roles in the formation of the nervous system along with the accumulated knowledge in non-neuronal systems.

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PubMedDate not supplied

Acute no-effect dose for in ova exposure to C3F7 tagged 5-hydroxytryptophan, a novel probe for investigating neural development.

PURPOSE: To create a probe for investigating neural development in chicks using magnetic resonance, a C(3)F(7) tag was bonded to the indole ring of 5-hydroxytryptophan (5-HTP). Immunoassays indicate that a low dose (5 microg/egg) administered in ova results in 0.5-1.0 microg accumulating in a 250 microL midbrain. PROCEDURES: Given the potential for developmental neurotoxicity of a compound that replaces an endogenous neurotransmitter, we investigated the effects of acute exposure during development. RESULTS: No qualitative differences were observed between treatment groups. Differences in mortality rates between treatment groups were not statistically significant [X(2)(obs)=2.30, X(2)(crit) (df=2)=5.99, P>.05]. CONCLUSION: The no-effect dose for in ova administration of C(3)F(7) tagged5-HTP is 5 microg/egg on Day 17.

5-Hydroxytryptophan↗

PubMed1993

Evolutionary change in neural development within the arthropods: axonogenesis in the embryos of two crustaceans.

It has been previously suggested that there is a conservative program for neural development amongst the arthropods, on the basis that a stereotyped set of cells involved in establishing the axon tracts in the CNS of insect embryos is also present in crayfish embryos. We have examined the spatiotemporal pattern of axon growth from a set of early differentiating central neurons in the embryo of two crustaceans, the woodlouse Porcellio scaber and the freshwater crayfish Cherax destructor, and drawn comparisons with insect neurons whose somata lie in corresponding positions within the CNS. While many of the woodlouse and crayfish neurons show a similar pattern of axon growth to their insect counterparts, the axon trajectories taken by others differ from those seen in insects. We conclude that this aspect of early neural development has not been rigidly conserved during the evolution of the crustaceans and insects. However, the extent of similarity between the insects and the crustaceans is consistent with the idea that these groups of arthropods share a common evolutionary 'Bauplan' for the construction of their nervous systems. While the pattern of early axon growth in the woodlouse and crayfish embryos is sufficiently similar that many neurons could be confidently recognised as homologues, several differences were noted in both the relative order of axon outgrowth and axon morphologies of individual neurons.

Animals↗

PubMed1988

Effects of altered expression of the neural cell adhesion molecule, N-CAM, on early neural development in Xenopus embryos.

The neural cell adhesion molecule, N-CAM, is known to be expressed very early in the development of the vertebrate nervous system. In frog embryos, N-CAM expression increases dramatically in ectoderm coincident with the formation of the neural plate and tube, suggesting that morphogenesis of the early nervous system is controlled in part by differential expression of N-CAM. This model was tested by introducing synthetic N-CAM transcripts into Xenopus embryos so that N-CAM was indiscriminately expressed at high levels on the surface of both induced and noninduced ectodermal cells throughout gastrulation and neurulation. Analysis of these embryos shows that high levels of N-CAM misexpression do not effect neural tube formation even though ectopic expression of N-CAM in epidermis and somitic mesoderm caused specific defects in the structure of these tissues. By showing that the properly regulated expression of N-CAM is not essential for neural tube formation, these results provide compelling evidence that N-CAM on its own does not act as a regulatory molecule during early neural development.

Animals↗

PubMed2006

The role of the MAGUK protein CASK in neural development and synaptic function.

CASK, which belongs to the family of membrane-associated guanylate kinase (MAGUK) proteins, is recognized as a multidomain scaffolding protein highly expressed in the mammalian nervous system. MAGUK proteins generally target to neuronal synapses and regulate trafficking, targeting, and signaling of ion channels. However, CASK is a unique MAGUK protein in several respects. It not only plays a role in synaptic protein targeting but also contributes to neural development and regulation of gene expression. Several CASK-interacting proteins have been identified from yeast two-hybrid screening and biochemical isolation. These proteins, whose interactions with CASK are reviewed here, include the Parkinson's disease molecule parkin, the adhesion molecule neurexin, syndecans, calcium channel proteins, the cytoplasmic adaptor protein Mint1, Veli/mLIN-7/MALS, SAP97, caskin and CIP98, transcription factor Tbr-1, and nucleosome assembly protein CINAP. More important, CASK may form different complexes with different binding partners and perform different functions. Among these interactions, CASK, Tbr-1, and CINAP can form a transcriptional complex regulating gene expression. Reelin and NMDAR subunit 2b (NR2b) genes have been identified as Tbr-1 target genes. Reelin is critical for neural development. NR2b is an important subunit of NMDAR, which plays important roles in neural function and neurological diseases. Regulation of reelin and NR2b expression suggests the potential roles of the Tbr-1-CASK-CINAP complex in neural activity, development, and disease. The functions of these CASK protein complexes are also discussed in detail in this review.

Animals↗

PubMed1996

Involvement of the neuregulins and their receptors in cardiac and neural development.

The neuregulin gene encodes a series of polypeptide growth factors that can influence the growth state of target vertebrate cells in culture. Recently, three studies have explored the in vivo function of the neuregulin signaling system in mice by disrupting the genes encoding the neuregulin ligand(1) and two of its receptors, ErbB2(2) and ErbB4(3). Each of the genes is essential for development, and aberrations in cardiac and neural development are particularly prominent in mutant embryos. The observed defects, together with the localization of expression of the neuregulin signaling components within these tissues, highlight a paracrine mechanism for neuregulin-mediated intercellular communication.

Animals↗

PubMed1991

Growth cone inhibition--an important mechanism in neural development?

Since the growth cone was first described a century ago by Cajal, considerable effort has been directed towards understanding the mechanisms responsible for its guidance. Traditionally, attention has focussed on the role of adhesive molecules in determining neural development. Recently, it has become apparent that inhibitory interactions may play a crucial part in axonal navigation. A common feature of inhibition seen in three model systems (peripheral nerve segmentation, retinotectal mapping and CNS/PNS segregation) is a collapse of the motile structures of the growth cone. It is increasingly clear that the identification of molecular mechanisms of inhibition, as well as those of adhesion, will be of fundamental importance to understanding neural development.

Animals↗

PubMed1998

The ephrins and Eph receptors in neural development.

The Eph receptors are the largest known family of receptor tyrosine kinases. Initially all of them were identified as orphan receptors without known ligands, and their specific functions were not well understood. During the past few years, a corresponding family of ligands has been identified, called the ephrins, and specific functions have now been identified in neural development. The ephrins and Eph receptors are implicated as positional labels that may guide the development of neural topographic maps. They have also been implicated in pathway selection by axons, the guidance of cell migration, and the establishment of regional pattern in the nervous system. The ligands are anchored to cell surfaces, and most of the functions so far identified can be interpreted as precise guidance of cell or axon movement. This large family of ligands and receptors may make a major contribution to the accurate spatial patterning of connections and cell position in the nervous system.

Animals↗

PubMed1998

Interleukin-1beta and its type 1 receptor are expressed in developing neural circuits in the frog, Xenopus laevis.

The cytokine interleukin-1 beta (IL-1beta) is an evolutionarily conserved molecule that was originally identified in the immune system. In addition to regulating peripheral immune responses, IL-1beta plays an important role in mediating neural-immune interactions and regulating glial activities during healing and repair in the damaged nervous system. Active IL-1beta is produced by interleukin-converting enzyme (ICE), a caspase thought to be involved in the induction of apoptosis. We report that, in the developing frog, Xenopus laevis, IL-1beta and the IL-1 type 1 receptor proteins are coexpressed in specific neurons that comprise early sensory-motor circuits. IL-1beta and IL-1 type 1 receptor proteins are colocalized in specific midbrain and hindbrain reticular cells, including Mauthner's neuron; specific cells in the trigeminal (fifth), lateral line (seventh), and vestibular (eighth) cranial ganglia; oculomotor neurons; and the primordial Purkinje cells of the lateral cerebellar auricle. In the spinal cord, Rohon-Beard sensory neurons, dorsal root ganglion cells, and primary motoneurons are immunopositive. Anteriorly, the olfactory pits, olfactory nerves, and olfactory bulbs are labeled, as are retinal cells, especially photoreceptor inner segments. With regard to the function of IL-1beta during neural development, IL-1beta and its type 1 receptor are present throughout the course of neural development in identifiable, long-lived neurons, such as Mauthner's neuron. These and other data suggest that IL-1beta and its type 1 receptor may be involved in the maintenance of cell survival rather than induction of neuronal death.

Animals↗

PubMed1996

The Le(x) carbohydrate sequence is recognized by antibody to L5, a functional antigen in early neural development.

The L5 antigenic determinant was previously suggested to be a carbohydrate epitope present on murine cell recognition molecules in the developing brain and to be an early neural marker in the chick embryo. Here, we show that L5 immunoreactivity is associated with complex-type N-glycosidic oligosaccharides. To identify the carbohydrate structure recognized by the L5 antibody, we investigate its binding to N-linked oligosaccharides derived from L5 glycoproteins and to known glycans. Results of mass spectrometric analyses of L5-positive neoglycolipids prepared from L5 glycoproteins are consistent with those for N-glycans containing a 3-fucosyl N-acetyllactosamine sequence. We also investigate L5 binding to structurally defined, lipid-linked oligosaccharides based on the blood group type I and II backbones. Chromatogram binding assays, ELISA, and inhibition studies show that the antibody reacts strongly with carbohydrate chains presenting the 3-fucosyl N-acetyllactosamine sequence [Lewisx (Le(x)) or X-hapten] also recognized by anti-SSEA-1 and anti-CD15. Histochemical studies with different antibodies recognizing the Lex sequence show partially overlapping patterns of immunoreactivity during early neural development in the chick embryo. Therefore, we suggest that the epitope recognized by L5 antibody is closely related to those for anti-SSEA-1 and anti-CD15.

Animals↗

PubMed2005

Toutatis, a TIP5-related protein, positively regulates Pannier function during Drosophila neural development.

The GATA factor Pannier (Pnr) activates proneural expression through binding to a remote enhancer of the achaete-scute (ac-sc) complex. Chip associates both with Pnr and with the (Ac-Sc)-Daughterless heterodimer bound to the ac-sc promoters to give a proneural complex that facilitates enhancer-promoter communication during development. Using a yeast two-hybrid screening, we have identified Toutatis (Tou), which physically interacts with both Pnr and Chip. Loss-of-function and gain-of-function experiments indicate that Tou cooperates with Pnr and Chip during neural development. Tou shares functional domains with chromatin remodelling proteins, including TIP5 (termination factor TTFI-interacting protein 5) of NoRC (nucleolar remodelling complex), which mediates repression of RNA polymerase 1 transcription. In contrast, Tou acts positively to activate proneural gene expression. Moreover, we show that Iswi associates with Tou, Pnr and Chip, and is also required during Pnr-driven neural development. The results suggest that Tou and Iswi may belong to a complex that directly regulates the activity of Pnr and Chip during enhancer-promoter communication, possibly through chromatin remodelling.

Adenosine Triphosphatases↗

PubMed1997

Thyroid hormone-dependent gene expression program for Xenopus neural development.

Although thyroid hormone (TH) plays a significant role in vertebrate neural development, the molecular basis of TH action on the brain is poorly understood. Using polymerase chain reaction-based subtractive hybridization we isolated 34 cDNAs for TH-regulated genes in the diencephalon of Xenopus tadpoles. Northern blots verified that the mRNAs are regulated by TH and are expressed during metamorphosis. Kinetic analyses showed that most of the genes are up-regulated by TH within 4-8 h and 13 are regulated by TH only in the brain. All cDNA fragments were sequenced and the identities of seven were determined through homology with known genes; an additional five TH-regulated genes were identified by hybridization with known cDNA clones. These include five transcription factors (including two members of the steroid receptor superfamily), a TH-converting deiodinase, two metabolic enzymes, a protein disulfide isomerase-like protein that may bind TH, a neural-specific cytoskeletal protein, and two hypophysiotropic neuropeptides. This is the first successful attempt to isolate a large number of TH-target genes in the developing vertebrate brain. The gene identities allow predictions about the gene regulatory networks underlying TH action on the brain, and the cloned cDNAs provide tools for understanding the basic molecular mechanisms underlying neural cell differentiation.

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