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PubMed2005

Chromatin remodeling in neural development and plasticity.

Neural stem cells generate distinct cell types for tissue formation and cell replacement during development and throughout adulthood. Neural development and plasticity are determined by both extrinsic and intrinsic factors that interface to regulate gene programs for controlling neuronal cell fate and function. Recent reports have shown that chromatin remodeling and epigenetic gene regulation play an important role in such diverse areas as neural cell fate specification and synaptic development and function. These epigenetic mechanisms include cell-type-specific transcriptional regulators, histone modifications and chromatin remodeling enzymes, and the activity of retrotransposons.

Chromatin Assembly and Disassembly↗
PubMed1996

Persistent expression of genes of the enhancer of split complex suppresses neural development in Drosophila.

The segregation of neural and epidermal progenitors in Drosophila requires the activity of transcription factors encoded by the proneural genes and the genes of the E(SPL)-C. Persistent expression of two genes of the E(SPL)-C suppresses neural development. Embryos exhibit conspicuous central neural hypoplasia and lack sensory organs; imaginal sensory organs are also affected. Suppression of neural development is associated with suppression of the activity of proneural genes. DNA binding is not essential for this effect. Large cells with characteristics of neuroblasts segregate normally in embryos, but these cells fail to express various markers, and the segregated cells and/or their progeny eventually die. These findings indicate that proneural and E(spl) proteins exert antagonistic functions.

Animals↗
PubMed2002

Molecular cloning and characterization of dullard: a novel gene required for neural development.

In a screen for genes expressed in neural tissues and pronephroi, we isolated a novel gene, named dullard. Dullard protein contains the C-terminal conserved domain of NLI-IF (Nuclear LIM Interactor-Interacting Factor), a protein whose function is not yet characterized. Dullard mRNA was maternally derived and localized to the animal hemisphere. At neurula stages, the expression was in neural regions and subsequently localized to neural tissues, branchial arches, and pronephroi. Using antisense morpholino oligonucleotide-mediated inhibition, we showed that dullard was required for neural development. The translational knock-down of dullard resulted in failure of neural tube development and the embryos consequently showed a reduction of head development. Expression of neural marker genes in dullard-inhibited embryos was also suppressed. These results suggest that dullard is necessary for neural development.

Amino Acid Sequence↗
PubMed2002

Gene expression profiling within the developing neural tube.

The developing mammalian nervous system is subject to devastating congenital malformations with clinical significance that extends into the billions of health care dollars annually worldwide. Neural tube defects (NTDs) are among the most common of all human congenital defects, yet their etiology remains poorly understood. This is largely due to the complexity of the genetic factors regulating the intricate events involved in neurulation. Using mouse model systems and the application of modern molecular biological technologies, we have recently gained a greater appreciation for the factors that not only regulate normal neural tube closure (NTC), but those genetic factors that predispose an embryo to significant birth defects such as anencephaly or spina bifida. We have selected prominent murine mutants, both spontaneous and genetically modified, as well as the use of teratogenic agents, to examine the impact of altering the normal pattern of gene expression in the developing neural tube.

Animals↗
PubMed1994

Models of activity-dependent neural development.

What makes a useful model of neural development? One important contribution of modeling is to demonstrate that proposed biological mechanisms can be sufficient to account for experimental results. The Von der Malsburg model is a classic example. But such demonstrations alone do not provide tools to experimentally distinguish one mechanism from another. To draw such distinctions, the connection between measurable biological quantities and developmental outcomes must be established. Perhaps the most important task for the future of developmental modeling is to deepen the connection between theory and experiment. Experimentally, this requires detailed and difficult measurements or experimental perturbations of the correlations among inputs and the intracortical connectivity existing during development. Simultaneous measurement of the maps of spatial phase and orientation of mature simple cells will provide important information for the understanding of orientation column development. Theoretically, the number of open problems is enormous. How will inclusion of additional plasticity mechanisms, such as sprouting and retraction of synapses or plasticity of intracortical connections, alter the analytical understanding thus far achieved? What precisely determines the width of orientation columns in the model presented here? Can the relationship between ocular dominance and orientation columns be understood from developmental rules in a testable way? The existing framework may be extended to a three-dimensional cortex and to more complex models of intracortical connectivity. It may also be applied to other developmental phenomena including the development of lamination in the LGN (Shatz and Stryker, 1988; Hahm et al., 1991), the formation of visual maps in experimentally altered auditory cortex (Roe et al., 1990, 1992), and the mapping of visual and auditory maps in the optic tectum (Knudsen and Brainard, 1991; Brainard and Knudsen, 1993). For each system the goal is to develop testable predictions as to the patterns of activity and connectivity that could or could not lead to the results observed given a proposed mechanism of plasticity. Incorporation of deeper levels of biophysical realism will extend, deepen, and perhaps fundamentally alter the framework presented here. An important goal for the future will be to understand the computational and functional significance of developmental rules. Activity-dependent, competitive mechanisms of synaptic plasticity appear to play an important role in many processes of late neural development, where an initially rough connectivity pattern refines to a precise, mature pattern. A prominent example is the formation of ocular dominance columns in the visual cortex of many mammals. These processes may be modeled at several levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Expression of surface glycoproteins early in leech neural development.

Cell migration and axon growth during neural development rely upon cell-cell and cell-matrix interactions mediated by surface glycoproteins. The surface glycoprotein recognized on leech neurons by monoclonal antibody Lan3-2 has previously been implicated in the process of axon fasciculation during regeneration in adults. In adult leeches, Lan3-2 binds to a carbohydrate epitope of a 130 kD protein. The present study demonstrates that in embryos the antibody binds to the same carbohydrate epitope of glycoproteins with molecular weights of 130 kD and higher. As a first step in evaluating a possible role of the Lan3-2 glycoprotein or the cells that express it during neural development, we determined its distribution in the developing nervous system of the leech Hirudo medicinalis. In embryos, Lan3-2 epitope is expressed on fasciculated sensory afferents and it appears on the cell bodies before neurite outgrowth. The sensory fibers appear rostrally by embryonic day 10, less than halfway through development. Earlier, by 7 days of development at 20 degrees C, Lan3-2 binds to previously undocumented cell types: (1) cells appearing along the embryonic midline and (2) a cluster of cells located at the rostral edge of the germinal plate. These cells only transiently express this antigen and are present at critical left-right and rostrocaudal boundaries during a period of cell proliferation, movement, and migration that produces the nervous system. Thus the Lan3-2 surface glycoprotein or the cells expressing it are candidates for involvement in axon fasciculation, cell migration, and directed axonal growth.

Animals↗
PubMed2006

Impaired neural development caused by inducible expression of Axin in transgenic mice.

Ablations of the Axin family genes demonstrated that they modulate Wnt signaling in key processes of mammalian development. The ubiquitously expressed Axin1 plays an important role in formation of the embryonic neural axis, while Axin2 is essential for craniofacial skeletogenesis. Although Axin2 is also highly expressed during early neural development, including the neural tube and neural crest, it is not essential for these processes, apparently due to functional redundancy with Axin1. To further investigate the role of Wnt signaling during early neural development, and its potential regulation by Axins, we developed a mouse model for conditional gene activation in the Axin2-expressing domains. We show that gene expression can be successfully targeted to the Axin2-expressing cells in a spatially and temporally specific fashion. High levels of Axin in this domain induce a region-specific effect on the patterning of neural tube. In the mutant embryos, only the development of midbrain is severely impaired even though the transgene is expressed throughout the neural tube. Axin apparently regulates beta-catenin in coordinating cell cycle progression, cell adhesion and survival of neuroepithelial precursors during development of ventricles. Our data support the conclusion that the development of embryonic neural axis is highly sensitive to the level of Wnt signaling.

Journal Article↗
PubMed2001

frizzled 9 is expressed in neural precursor cells in the developing neural tube.

The wnt signaling pathway has important functions in nervous system development. To better understand this process we have cloned and analyzed the expression of the wnt receptor, frizzled 9, in the developing nervous system in mouse, chick and zebrafish. The earliest expression of mouse frizzled 9 mRNA expression begins at E8.5 with expression throughout the entire rostral-caudal neuraxis. This early expression pattern within the neural tube appears to be conserved between chick and zebrafish. Expression becomes restricted to a ventral domain in the mouse ventricular zone at E11.5, a region specified to give rise to neurons and glia. Using a polyclonal antibody to MFZ9 further shows expression limited to neural restricted precursors cells.

Animals↗
PubMed2005

Wnt signaling: multiple functions in neural development.

Wnt signaling has proven to be essential for neural development at various stages and across species. Wnts are involved in morphogenesis and patterning, and their proliferation-promoting role is a key function in stem cell maintenance and the expansion of progenitor pools. Moreover, Wnt signaling is involved in differentiation processes and lineage decision events during both central and peripheral nervous system development. Additionally, several reports point to a role of Wnt signaling in axon guidance and neurite outgrowth. This article reviews and consolidates the existing evidence for the functions of Wnt signaling in neural development.

Animals↗
PubMed1998

Cell fate specification in an in vitro model of neural development.

We have studied in an in vitro model of neural development the effect of neighboring cells on the fate of single fluorescently labeled precursor cells. In one line of experiments, PCC7-Mz1 embryonal carcinoma cells were transiently transfected with "green fluorescent protein" (GFP) and, following incubation with 0.1 microM all-trans retinoic acid (RA), the number and morphology of derivatives (neuronal or non-neuronal) was determined that form groups of GFP-expressing cells in a surrounding of unlabeled cells. Because single PCC7-Mz1 cells can produce single-lineage and mixed-lineage derivatives, they are individually pluripotent. In another line of experiments, we have analyzed the fate of GFP-expressing PCC7-MzN cells in different cellular environments. Whereas in the absence of other cells, PCC7-MzN cells exclusively differentiated to neuronal derivatives following RA induction (Lang, E., M. L. Mazauric-Stüker, A. Maelicke, J. Cell Biol. 109, 2481-2493 (1989)), they differentiated also to non-neuronal phenotypes (astrocytes and fibroblasts) when co-cultured with either PCC7-Mz1 stem cells or freshly RA-induced cells. The fate of PCC7-MzN cells could also be shifted in the absence of other cells when the cells were grown on laminin-coated surfaces. These results suggest that a putative fate-shifting activity (FSA) is released by PCC7-Mz1 and PCC7-MzN cells which requires, at least in the case of MzN cells, presentation by extracellular matrix-like structures in order to function in cell fate specification. Very few other cell types, in particular primary cultures of mouse forebrain cells of embryonic day 13, were capable of shifting the developmental potential of PCC7-MzN cells in a similar manner as PCC7-Mz1 cells do. We conclude that cell type specification in this model of neural development may occur by similar mechanisms as have been established in Drosophila neurogenesis. A default pathway (neuronal) is modulated by lateral signaling between neighboring cells so that cellular diversity can arise from initially homogeneous populations of progenitor cells.

3T3 Cells↗
PubMed2002

Inhibition of BMP activity by the FGF signal promotes posterior neural development in zebrafish.

The expression patterns of region-specific neuroectodermal genes and fate-map analyses in zebrafish gastrulae suggest that posterior neural development is initiated by nonaxial signals, distinct from organizer-derived secreted bone morphogenetic protein (BMP) antagonists. This notion is further supported by the misexpression of a constitutively active form of zebrafish BMP type IA receptor (CA-BRIA) in the zebrafish embryos. It effectively suppressed the anterior neural marker, otx2, but not the posterior marker, hoxb1b. Furthermore, we demonstrated that the cells in the presumptive posterior neural region lose their neural fate only when CA-BRIA and Xenopus dominant-negative fibroblast growth factor (FGF) receptors (XFD) are coexpressed. The indications are that FGF signaling is involved in the formation of the posterior neural region, counteracting the BMP signaling pathway within the target cells. We then examined the functions of Fgf3 in posterior neural development. Zebrafish fgf3 is expressed in the correct place (dorsolateral margin) and at the correct time (late blastula to early gastrula stages), the same point that the most precocious posterior neural marker, hoxb1b, is first activated. Unlike other members of the FGF family, Fgf3 had little mesoderm-inducing activity. When ectopically expressed, Fgf3 expands the neural region with suppression of anterior neural fate. However, this effect was mediated by Chordino (zebrafish Chordin), because Fgf3 induces chordino expression in the epiblast and Fgf3-induced neural expansion was substantially suppressed in dino mutants with mutated chordino genes. The results obtained in the present study reveal multiple actions of the FGF signal on neural development: it antagonizes BMP signaling within posterior neural cells, induces the expression of secreted BMP antagonists, and suppresses anterior neural fate.

Animals↗
PubMed2000

Cell death in early neural development: beyond the neurotrophic theory.

The important effect of cell death on projecting neurons during development is well established. However, this mainstream research might have diverted recognition of the cell death that occurs at earlier stages of neural development, affecting proliferating neural precursor cells and young neuroblasts. In this article, we briefly present observations supporting the occurrence of programmed cell death during early neural development in a regulated fashion that to some extent parallels the death of projecting neurons lacking neurotrophic support. These findings raise new questions, in particular the magnitude and the role of this early neural cell death.

Animals↗
PubMed1999

Morphogenic role for acetylcholinesterase in axonal outgrowth during neural development.

Acetylcholinesterase (AChE) is the enzyme that hydrolyzes the neurotransmitter acetylcholine at cholinergic synapses and neuromuscular junctions. However, results from our laboratory and others indicate that AChE has an extrasynaptic, noncholinergic role during neural development. This article is a review of our findings demonstrating the morphogenic role of AChE, using a neuronal cell culture model. We also discuss how these data suggest that AChE has a cell adhesive function during neural development. These results could have additional significance as AChE is the target enzyme of agricultural organophosphate and carbamate pesticides as well as the commonly used household organophosphate chlorpyrifos (Dursban). Prenatal exposure to these agents could have adverse effects on neural development by interfering with the morphogenic function of AChE.

Acetylcholinesterase↗
PubMed2004

The role of Zic genes in neural development.

The Zic family of zinc-finger proteins plays a crucial role in neural development. Zic genes are vertebrate homologs of odd-paired, the Drosophila pair-rule gene. Their gene products have zinc-finger domains similar to those of Gli proteins, which act as transcriptional regulators in hedgehog signaling. Recent studies of human, mouse, frog, fish and ascidian Zic homologs have provided evidence that Zic genes are involved in a variety of developmental processes, including neurogenesis, myogenesis, skeletal patterning, and left-right axis establishment. Zic genes appear to have multiple roles in neural development. They control the initial phase during which ectoderm differentiates into neuroectoderm, and they may act as bridges between secreted neural tissue induction signals and the basic-helix-loop-helix class of neurogenesis-inducing transcriptional regulatory factors. Studies of loss-of-function mutations with differing Zic gene subtypes show that the Zic family of genes controls the process of neurulation. Mutations result in neural tube defects, which are seen at different rostrocaudal levels depending on which Zic gene subtype has been affected. Development of holoprosencephaly, forebrain anomalies, and cerebellar dysgenesis indicate that region-specific morphogenesis of the CNS is also controlled by Zic genes. The underlying molecular actions of Zic gene products, which allow them to control development, remain a mystery. Recent molecular characterization has shown that Zic proteins are able to bind Gli-binding DNA sequences in a sequence-specific manner, but with lower affinity than Gli proteins. Zic proteins also can activate transcription from several promoters. Furthermore, Zic and Gli proteins interact physically via their zinc-finger domains, raising the possibility that Zic proteins can act as transcriptional cofactors and modulate the hedgehog-signaling pathway. Clarification of the specific cooperating factors is therefore required in each case. Other evidence also suggests that Zic proteins can inhibit neuronal differentiation by activating Notch signals. This association might be is a clue toward understanding of the multifunctional property of Zic proteins because Notch signaling also is implicated in the control of several developmental processes.

Animals↗
PubMed2001

Trk receptor tyrosine kinases: a bridge between cancer and neural development.

The proto-oncogene Trks encode the high-affinity receptor tyrosine kinases for neurotrophins of a nerve growth factor (NGF) family. The Trk signals spatiotemporally regulate neural development and maintenance of neural network. However, Trk was originally cloned as an oncogene fused with the tropomyosin gene in the extracellular domain. Accumulating evidence has demonstrated that the rearranged Trk oncogene is often observed in non-neuronal neoplasms such as colon and papillary thyroid cancers, while the signals through the receptors encoded by the proto-oncogene Trks regulate growth, differentiation and apoptosis of the tumors with neuronal origin such as neuroblastoma and medulloblastoma. The intracellular Trk signaling pathway is also different depending on the Trk family receptors, cell types and the grade of transformation. Furthermore, developmentally programmed cell death of neuron, which is largely regulated by neurotrophin signaling, is at least in part controlled by tumor suppressors p53 and p73 as well as their antagonist DeltaNp73. Thus, the Trks and their downstream signaling function in both ontogenesis and oncogenesis. In this short review, the dynamic role of the Trk family receptors signaling in neural development, neurogenic tumors and other cancers will be discussed.

Animals↗
PubMedDate not supplied

Neural development. FESN Study Group.

The FESN-sponsored follow-up meeting on neural development highlighted progress toward understanding several central issues in developmental neurobiology with particular emphasis on investigation into the mechanisms of cell fate determination. In systems as diverse as the HSN neurons of C. elegans, the photoreceptor cells of the Drosophila eye, the wide range of cell types within the vertebrate retina and the neurons of the cerebral cortex, hindbrain and spinal cord, the importance of environment in the determination and maintenance of cell fate was clearly established. Advances in cell marking techniques, including fluorescent dye and retroviral tagging, have enabled the fates of cells in normal and heterotypic environments to be followed and have demonstrated the initial plasticity of the progenitor cell population in many systems. The recent establishment of in vitro systems for studying neural development should further define the precise nature and identity of the environmental signals that act to establish and maintain cell fate. Of course, establishment of cell identity is only the initial phase in the formation of the mature nervous system. Once the fate of individual cells is determined, migration of cells to appropriate locations, extension of axons to appropriate targets and refinement of neuronal circuitry must occur. Both the definition of genes that influence these processes in nematodes and recent advances in imaging techniques that provide a means of observing these later, dynamic processes in 'living' brain slices promise to significantly advance understanding of the complexities of development of functional nervous systems.

Animals↗
PubMed1992

Molecular bases of early neural development in Xenopus embryos.

Genes that are differentially expressed in the ectoderm as it diverts along the neural and epidermal pathways of differentiation can be used to study the inducing signals underlying induction as well as how ectoderm responds to these signals by forming neural tissue. Although these genes have provided, and will continue to provide, new information about the induction process, they are not likely to provide the whole story. For example, Notch is a gene required for neurogenesis in Drosophila embryos. When the Notch gene product is absent, the embryo forms far too many neuroblasts at the expense of the hypodermal cell layer (Artavanis-Tsakonis 1988, Campos-Ortega 1988). Even though Notch appears to play a role in deciding the fate of neural/hypodermal cells, the Notch gene product is expressed ubiquitously in early embryos in the neurogenic region (Hartley et al 1987, Kidd et al 1989). Thus, one possibility is that Notch function does not necessarily depend on differential expression of the Notch gene product within cells in the neurogenic regions [although an alternative view has been suggested by Greenspan (1990)]. Thus, some of the molecules controlling early neural development may not be expressed differentially when the ectoderm forms the neural plate. Obviously, other approaches will have to be taken to isolate and characterize these molecules. In this light, it is noteworthy that a molecule has been identified in Xenopus that is remarkably similar to Drosophila Notch in both structure and developmental expression (Coffman et al 1990). One hope is that the analysis of this molecule in combination with the molecules that are differentially expressed during neural induction will eventually lead to a molecular understanding of early neural development in vertebrate embryos.

Animals↗