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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In examining the role of Class 3 secreted semaphorins in the prenatal and postnatal development of the septohippocampal pathway, we found that embryonic (E14-E16) septal axons were repelled by the cingulate cortex and the striatum. We also found that the hippocampus exerts chemorepulsion on dorsolateral septal fibers, but not on fibers arising in the medial septum/diagonal band complex, which is the source of septohippocampal axons. These data indicate that endogenous chemorepellents prevent the growth of septal axons in nonappropriate brain areas and direct septohippocampal fibers to the target hippocampus. The embryonic septum expressed np-1 and np-2 mRNAs, and the striatum and cerebral cortex expressed sema 3A and sema 3F. Experiments with recombinant semaphorins showed that Sema 3A and 3F, but not Sema 3C or 3E, induce chemorepulsion of septal axons. Sema 3A and 3F also induce growth cone collapse of septal axons. This indicates that these factors are endogenous cues for the early guidance of septohippocampal fibers, including cholinergic and gamma-aminobutyric acid (GABA)ergic axons, during the embryonic stages. During postnatal stages, when target cell selection and synaptogenesis take place, np-1 and np-2 were expressed by septohippocampal neurons at all ages tested. In the target hippocampus, pyramidal and granule cells expressed sema 3E and sema 3A, whereas most interneurons expressed sema 3C, but few expressed sema 3E or 3A. Combined tracing and expression studies showed that GABAergic septohippocampal fibers terminated preferentially onto sema 3C-positive interneurons. In contrast, cholinergic septohippocampal fibers terminated onto sema 3E and sema 3A-expressing pyramidal and granule cells. The data suggest that Class 3 secreted semaphorins are involved in postnatal development. Moreover, because GABAergic and cholinergic axons terminate onto neurons expressing distinct, but overlapping, patterns of semaphorin expression, semaphorin functions may be regulated by different signaling mechanisms at postnatal stages.
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PMID:Role of class 3 semaphorins in the development and maturation of the septohippocampal pathway. 1538 96

A secreted semaphorin, Sema3A, is an axon guidance molecule that induces collapse of growth cones and repels axons in vitro. Neuropilin-1 (Nrp-1) is a receptor for Sema3A. To clarify the function of the semaphorin in vivo, we generated Sema3A mutant mice and Nrp-1 mutant mice by targeted disruption of the Sema3A and Nrp-1 genes, respectively. These mutant mouse embryos showed a severe defect in the trajectory and projection of PNS efferent, suggesting that the Nrp-1-mediated Sema3A signals play crucial roles in the directional guidance of nerve fibers and the establishment of PNS networks. The deprivation of Nrp-1-mediated Sema3A signals also induced disorganization of the sympathetic nervous system. In the Nrp-1 and Sema3A mutant mouse embryos, more than half of the TH-positive SG neurons were distributed at ectopic positions. As a whole, the sympathetic trunk was severely disorganized. Sema3 A recombinant proteins inhibited migration of the wild-type (Nrp-1-expressing) but not Nrp-1-deficient SG neurons in culture, suggesting that Nrp-1-mediated Sema3A inhibitory signals are essential in precise migration of SG neurons, as well as directional guidance of axons.
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PMID:[Roles of semaphorins in neuron network formation]. 1548 18

It has been proposed that four members of the plexin A subfamily (plexin-As; plexin-A1, -A2, -A3, and -A4) and two neuropilins (neuropilin-1 and neuropilin-2) form complexes and serve as receptors for class 3 secreted semaphorins (Semas), potent neural chemorepellents. The roles of given plexin-As in semaphorin signaling and axon guidance, however, are mostly unknown. Here, to elucidate functions of plexin-A4 in semaphorin signaling and axon guidance events in vivo, we generated plexin-A4 null mutant mice by targeted disruption of the plexin-A4 gene. Plexin-A4 mutant mice were defective in the trajectory and projection of peripheral sensory axons and sympathetic ganglion (SG) axons and the formation of the anterior commissure and the barrels. The defects in peripheral sensory and SG axons were fundamentally related to those of neuropilin-1 or Sema3A mutant embryos reported but were more moderate than the phenotype in these mutants. The growth cone collapse assay showed that dorsal root ganglion axons and SG axons of plexin-A4 mutant embryos partially lost their responsiveness to Sema3A. These results suggest that plexin-A4 plays roles in the propagation of Sema3A activities and regulation of axon guidance and that other members of the plexin-A subfamily are also involved in the propagation of Sema3A activities. Plexin-A4-deficient SG axons did not lose their responsiveness to Sema3F, suggesting that plexin-A4 serves as a Sema3A-specific receptor, at least in SG axons. In addition, the present study showed that plexin-A4 bound class 6 transmembrane semaphorins, Sema6A and Sema6B, and mediated their axon-repulsive activities, independently of neuropilin-1. Our results imply that plexin-A4 mediates multiple semaphorin signals and regulates axon guidance in vivo.
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PMID:Plexin-a4 mediates axon-repulsive activities of both secreted and transmembrane semaphorins and plays roles in nerve fiber guidance. 1581 94

Abstract In the spinal cord, motor neurons (MNs) with similar muscle targets and sensory inputs are grouped together into motor pools. To date, relatively little is known about the molecular mechanisms that control the establishment of pool-specific circuitry. Semaphorins, a large family of secreted and cell surface proteins, are important mediators of developmental processes such as axon guidance and cell migration. Here, we used mRNA in situ hybridization to study the expression patterns of semaphorins and their receptors, neuropilins and plexins, in the embryonic mouse spinal cord. Our data show that semaphorins and their receptors are differentially expressed in MNs that lie in distinct locations within the spinal cord. Furthermore, we report a combinatorial expression of class 3 (secreted) semaphorins and their receptors that characterizes distinct motor pools within the brachial and lumbar spinal cord. Finally, we found that a secreted semaphorin, Sema3A, elicits differential collapse responses in topologically distinct subpopulations of spinal MNs. These findings lead us to propose that semaphorins and their receptors might play important roles in the sorting of motor pools and the patterning of their afferent and efferent projections.
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PMID:A semaphorin code defines subpopulations of spinal motor neurons during mouse development. 1586 72

Myosin II is an intracellular force-generating enzyme with no known extracellular action. In the course of experiments involving trituration loading of skeletal myosin II into embryonic sensory neurons we observed that extracellular application of myosin II to neurons resulted in a robust increase in the number of axons initiated by each neuron, but did not alter the rate of axon extension. Substratum bound myosin II in the presence of laminin was sufficient to elicit increases in axon formation. However, in the absence of laminin, extracellular myosin II alone was not sufficient to promote axon formation, although it allowed neuron survival in the presence of neurotrophin. Myosin II promoted the attachment of neurons to the substratum in the absence or presence of laminin. In addition to promoting the initiation of axons, extracellular myosin II also increased the frequency of axon collateral branching. Finally, extracellular myosin II did not affect growth cone collapse in response to semaphorin-IIIA, but attenuated the inhibitory action of chondroitin sulfate proteoglycans on axon extension. Surprisingly, these results demonstrate that extracellular myosin II promotes attachment of neurons and increases axon formation and branching. The potential significance of these observations is discussed in the context of myosin II release from injured muscle and a previous demonstration of extracellular myosin II association with the extracellular matrix.
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PMID:Extracellular Muscle Myosin II Promotes Sensory Axon Formation. 1600 12

Plexins are transmembrane receptors for semaphorins, guiding cell migration and axon extension. Plexin activation leads to the disassembly of integrin-based focal adhesive structures and to actin cytoskeleton remodelling and inhibition of cell migration; however, the underlying molecular mechanisms are unclear. We consistently observe a transient decrease of cellular RhoA-GTP levels upon plexin activation in adherent cells. One of the main effectors of RhoA downregulation is p190, a ubiquitously expressed GTPase activating protein (GAP). We show that, in p190-deficient fibroblasts, the typical functional activities mediated by plexins (such as cell collapse and inhibition of integrin-based adhesion) are blocked or greatly impaired. Notably, the functional response can be rescued in these cells by re-expressing exogenous p190, but not a mutant form specifically lacking RhoGAP activity. We furthermore demonstrate that semaphorin function is blocked in epithelial cells, primary endothelial cells and neuroblasts upon treatment with small interfering RNAs that knockdown p190 expression. Finally, we show that p190 transiently associates with plexins, and its RhoGAP activity is increased in response to semaphorin stimulation. We conclude that p190-RhoGAP is crucially involved in semaphorin signalling to the actin cytoskeleton, via interaction with plexins.
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PMID:p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signalling. 1618 38

Axon guidance represents an important step in the formation of neuronal networks. Axons are guided by various guidance factors, such as semaphorins, slits, ephrins, and netrins. Plexins are cell surface receptors for the repulsive molecules of the semaphorin family. Cytoplasmic regions of plexins are responsible for initiating cellular signal transduction, resulting in axon repulsion. Recent advances have shed light on the signal transduction mechanism of plexins and the mechanisms by which it leads to a repulsive response. Plexin-B1 possesses an intrinsic guanine triphosphate (GTP)ase activating protein activity for R-Ras, a member of Ras family of small GTPases that has been implicated in promoting cell adhesion and neurite outgrowth through integrin activation. Stimulation of Plexin-B1 by Sema4D induces collapse of the growth cone through downregulation of R-Ras activity. This article summarizes current understanding of the signaling mechanisms of plexins.
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PMID:R-ras as a key player for signaling pathway of plexins. 1638 38

Higher organisms rely on multiple modes of memory storage using the hippocampal network, which is built by precisely orchestrated mechanisms of axonal outgrowth, guidance and synaptic targeting. We demonstrate essential roles of the transcription factor serum response factor (SRF), a sensor of cytoskeletal actin dynamics, in all these processes. Conditional deletion of the mouse Srf gene reduced neurite outgrowth and abolished mossy fiber segregation, resulting in ectopic fiber growth inside the pyramidal layer. SRF-deficient mossy fibers aberrantly targeted CA3 somata for synapse formation. Axon guidance assays showed that SRF was a key mediator of ephrin-A and semaphorin guidance cues; in SRF-deficient neurons, these resulted in the formation of F-actin-microtubule rings rather than complete growth cone collapse. Dominant-negative variants of the SRF cofactor megakaryocytic acute leukemia (MAL) severely impeded neurite outgrowth and guidance. These data highlight essential links between SRF-mediated transcription and axon guidance and circuit formation in the hippocampus.
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PMID:Serum response factor controls neuronal circuit assembly in the hippocampus. 1641 69

Semaphorins are a family of growth cone guidance molecules. When associated with their receptors and coreceptors, plexins and neuropilins, they act as chemorepellents for an extensive range of neuronal populations. The prototypic semaphorin, Sema3A, has a potent inhibitory effect on sensory axons emanating from dorsal root ganglia. This has formed the basis of the most famous assay for semaphorin activity, the chick dorsal root ganglia collapse assay. Recently, a heterologous, highly tractable assay has been used to investigate semaphorin signaling. In this system, the binding of recombinant semaphorins to COS cells expressing plexins and neuropilins induces a morphological collapse that may correlate with growth cone collapse. This chapter describes the optimization of this assay and outlines the subtle differences required to enable Sema3A-Fc and Sema4D-Fc to induce identical collapse phenotypes in COS cells expressing Plexin-A1 and neuropilin-1, or Plexin-B1, respectively.
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PMID:Plexin-induced collapse assay in COS cells. 1647 96

The functioning of the vertebrate brain depends on the differentiation and positioning of the neural cells, and on the specific connections these cells make among themselves and their peripheral targets. Semaphorin3A (Sema3A), a secreted type of guidance cue of the semaphorin family, possesses a strong repulsive activity to a subset of neurons such as dorsal root ganglia and sympathetic neurons. CRMP (collapsin response mediator protein) was originally identified as an intracellular mediator of Sema3A by using Xenopus laevis oocyte expression system, but its mechanism has long been ill-defined. We demonstrate that Fyn-Cdk5 complex acts as a downstream mediator of Sema3A signaling cascades that induce growth cone collapse. In addition, the sequential phosphorylation of CRMP2 by Cdk5 and GSK3beta is an important process of Sema3A signaling. Since the dual-phosphorylated CRMP2 is recognized with the antibody 3F4, a highly reactive antibody with the neurofibrillary tangles of Alzheimer's disease, the same mechanism for Sema3A signaling may have some relevance to the pathological aggregation of the microtubule-associated proteins.
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PMID:[Molecular mechanism of axon guidance]. 1686 15


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