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Dorsoventral patterning of somites into sclerotome and dermomyotome involves antagonistic actions of ventralizing and dorsalizing signals originating from tissues surrounding the somites. The notochord and the floor plate of the neural tube provide a ventralizing signal(s) directing sclerotome development, whereas the surface ectoderm and dorsal neural tube provide a dorsalizing signal(s) directing dermomyotome development. Evidence has been provided that Sonic Hedgehog mediates the ventralizing effects of notochord and floor plate, but the dorsalizing signal(s) that patterns the dermomyotome has not been identified. The documented expression of Wnt1 and Wnt3a in the dorsal neural tube and of Wnt4 and Wnt6 in the surface ectoderm at the time of dermomyotome specification prompted us to investigate the involvement of WNT proteins in patterning the dermomyotome. Here we show that tissue culture cells expressing these WNT family members can maintain and induce dermomyotome marker expression in presomitic mesoderm explants, supporting the hypothesis that WNT proteins mediate the dorsalizing effects of the surface ectoderm and dorsal neural tube on somites. Key Words: somite; dermomyotome; patterning; Wnt, SHH.

Expression cloning was conducted to identify the Collapsin-1/Semaphorin III/D (Sema III)-binding proteins in embryonic rat sensory neurons and determine the axonal chemorepellent mechanisms of Sema III. Results show that Sema III's chemorepellent ability is inhibited by neuropilin antibodies. Results reveal that neuropilin is a receptor or a receptor complex component that degrades Sema III's effects on axons.

Cues in the extracellular environment of the nervous system guide migrating cells and axons to their targets. Netrins are cues that can function as attractants and repellents. In Caenorhabditis elegans, UNC-5, a transmembrane protein, has been implicated in certain responses, with the loss of unc-5 function leading to migration defects. A report identifies two UNC-5 vertebrate homologues, defining a new immunoglobulin subfamily. This indicates that the UNC-5 homologues and the mouse rostral cerebellar malformation gene are netrin-binding proteins.

The Deleted in colorectal cancer (DCC) gene was identified as a potential tumour-suppressor gene on human chromosome 18q, although it has not been conclusively implicated as the colorectal tumour-suppressor gene. Investigations indicate that DCC is an axonal chemoattractant netrin-1 receptor. The effects of inactivation of the mouse homologue of DCC are similar to those in netrin-1-deficient mice.

Netrin-1 is a large soluble protein that directs the circumferential axonal projections in vertebrates during the development of the vertebrate nervous system. The protein is expressed in the floor plate for directing the formation of the fimbria, hippocampal commissure, corpus callosum and anterior commissure. Furthermore, embryonic mice with deficient netrin-1 proteins due to the mutation of the netrin-1 allele exhibited defective spinal cord, hippocampal commissure and anterior commissure development.

Neuronal growth cones navigate over long distances along specific pathways to find their correct targets. The mechanisms and molecules that direct this pathfinding are the topics of this review. Growth cones appear to be guided by at least four different mechanisms: contact attraction, chemoattraction, contact repulsion, and chemorepulsion. Evidence is accumulating that these mechanisms act simultaneously and in a coordinated manner to direct pathfinding and that they are mediated by mechanistically and evolutionarily conserved ligand-receptor systems., The remarkable feats of information-processing performed by the brain are determined to a large extent by the intricate network of connections between nerve cells (or neurons). The magnitude of the [...]

The effects of netrin-1 on commisural axions of chicks are mediated by the Deleted in Colorectal Cancer (DCC) gene via cellular signal transduction pathway. The DCC gene is a netrin-1 binding protein that is expressed on the axons and growth cones of spinal commissural neurons during their migration to the floor plate. The binding protein also acts as a receptor during the guidance of commissural axons from the dorsal to the ventral midline region of the spinal cord.

An early and selective molecular marker for lateral somitic cells in the chick, cSim1, was identified. Genetic analyses showed cSim1 is an avian homolog of the Drosophila single minded (sim) gene. With this marker, it was shown that factors produced by the lateral plate activates cSim1 expression in the lateral somitic cells, which is counteracted by diffusible signals from the neural tube and from the lateral plate mesoderm. It is suggested that the bone morphogenic protein produced by the lateral plate cells directs the specification of the lateral somitic lineage.

Graded spatial distributions of the factors on the optic tectum provide positional information that is detected by receptor tyrosine kinases on axons to direct topographic map formation. The Eph family of receptor tyrosine kinases mediates contact repulsion of axons and provides the diversity of signals necessary to mediate distinct and specific recognition events throughout the nervous system. The Eph family provides one of the long-sought keys to understand topographic map formation.

Examination of the dorsal migration of trochlear motor axons using explant culture of the entire hindbrain-midbrain junction from rat embryos revealed that floor plate cells repel trochlear motor axons at a distance in vivo. Movement was guided by netrin-1, a long-range chemoattractant that has been established to guide axons ventrally from the floor plate. Netrin-1 was observed to share functions with the UNC-6 protein found in C. elegans, which guides dorsal migrations. These results suggest that netrin-1 is a bifunctional long-range guidance cue that attracts ventrally directed axons and repels dorsally directed axons.

In vivo studies indicate the presence of a single conserved signalling pathway for both local and direct long-range inductions of hedgehog proteins. The amino-terminal cleavage product(SHH-N) of the sonic hegehog gene causes the long-range sclerotome induction and dermomyotome repression in somite differentiation by the notochord. Increased activity of cyclic AMP-dependent protein kinase A decreases the activity of SHH-N.

Analysis of the mechanisms responsible for the growth of ventral neurons by examining the growth of dopaminergic (DA) neurons that are present near the motoneurons in ventral midbrain shows that DA neurons grow near the floor plate, which specifies the neurons in vivo and in vitro. Association with floor plate cells is essential for the activation of DA neuronal growth. Thus, the combined function of the contact-dependent and diffusible signals from the floorplate is capable of inducing neuronal diversification in the dorsal-ventral axis.

Analysis of cell growth in explanted mouse presomitic mesoderm to determine signals that are responsible for scelerotome and dermomyotome development shows that a diffusible form of Sonic hedgehog (Shh/Vhh-1) causes sclerotome induction while both ventralizing and dorsalizing signals cooperatively induce dorsoventral patterning of the somites. Floor plate and notochord produce the diffusible ventralizing signal that induces the sclerotomal markers. The dorsal neural tube and surface ectoderm produce the dorsalizing signals that induce the dermomyotomal markers.

Netrin-1 and -2 are specific proteins in embryonic chick brain membranes that act synergistically to axonal growth cones. The netrins have sequences homologous to the UNC-6 gene product of Caenorhabditis elegans and the laminin protein, which are involved in circumferential migration of growth cones. The C domains of netrins have sizable basic residues and control the adhesion of netrins to glycolipids on the neural cell surface.

Netrin-1 protein is a chemotropic agent present in floor plate cells of the embryonic nervous system. Netrin-1 and netrin-2 modulate commissural axon growth in the ventral midline of the spinal cord. The mediation of commissural axon growth by netrins requires a chemotropic mechanism. Extracellular matrix molecule modulators such as laminin serve as chemotropic factors. The netrin-2 transcripts are expressed at significantly low levels in comparison with netrin-1 transcripts during the early stages of spinal cord development.

The floor plate is a specialized group of midline neuroepithelial cells that appears to regulate cell differential and axonal growth in the developing vertebrate nervous system. A floor plate-specific chemorattractant [...]

Axon guidance molecules and neuronal activity have been implicated in the establishment and refinement of neural circuits during development. It is unclear, however, whether these guidance molecule- and activity-dependent mechanisms interact with one another to shape neural circuit formation. The formation of corticospinal (CS) circuits, which are essential for voluntary movements, involves both guidance molecule- and activity-dependent components during development. We previously showed that semaphorin6D (Sema6D)-plexinA1 (PlexA1) signaling eliminates ipsilateral projections of CS neurons in the spinal cord, while other studies demonstrate that CS projections to the spinal cord are eliminated in an activity-dependent manner. Here we show that inhibition of cortical neurons during postnatal development causes defects in elimination of ipsilateral CS projections in mice. We further show that mice that lack the activity-dependent Bax/Bak pathway or caspase-9 similarly exhibit defects in elimination of ipsilateral CS projections, suggesting that the activity-dependent Bax/Bak-caspase-9 pathway is essential for the removal of ipsilateral CS projections. Interestingly, either inhibition of neuronal activity in the cortex or deletion of Bax/Bak in mice causes a reduction in PlexA1 protein expression in corticospinal neurons. Finally, intracortical microstimulation induces activation of only contralateral forelimb muscles in control mice, whereas it induces activation of both contralateral and ipsilateral muscles in mice with cortical inhibition, suggesting that the ipsilaterally projecting CS axons that have been maintained in mice with cortical inhibition form functional connections. Together, these results provide evidence of a potential link between the repellent signaling of Sema6D-PlexA1 and neuronal activity to regulate axon elimination. [ABSTRACT FROM AUTHOR]

The two sides of the nervous system coordinate and integrate information via commissural neurons, which project axons across the midline. Commissural neurons in the spinal cord are a highly heterogeneous population of cells with respect to their birthplace, final cell body position, axonal trajectory, and neurotransmitter phenotype. Although commissural axon guidance during development has been studied in great detail, neither the developmental origins nor the mature phenotypes of commissural neurons have been characterized comprehensively, largely due to lack of selective genetic access to these neurons. Here, we generated mice expressing Cre recombinase from the Robo3 locus specifically in commissural neurons. We used Robo3Cre mice to characterize the transcriptome and various origins of developing commissural neurons, revealing new details about their extensive heterogeneity in molecular makeup and developmental lineage. Further, we followed the fate of commissural neurons into adulthood, thereby elucidating their settling positions and molecular diversity and providing evidence for possible functions in various spinal cord circuits. Our studies establish an important genetic entry point for further analyses of commissural neuron development, connectivity, and function. [ABSTRACT FROM AUTHOR]