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Guidance Molecules (guidance + molecule)
Kinds of Guidance Molecules Selected AbstractsRepulsive guidance molecule/neogenin: a novel ligand-receptor system playing multiple roles in neural developmentDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 6 2004Eiji Matsunaga The repulsive guidance molecule (RGM) is a membrane-bound protein originally isolated as an axon guidance molecule in the visual system. Recently, the transmembrane protein, neogenin, has been identified as the RGM receptor. In vitro analysis with retinal explants showed that RGM repels temporal retinal axons and collapses their growth cones through neogenin-mediated signaling. However, RGM and neogenin are also broadly expressed at the early embryonic stage, suggesting that they do not only control the guidance of visual axons. Gene expression perturbation experiments in chick embryos showed that neogenin induces cell death, and its ligand, RGM, blocks the pro-apoptotic activity of neogenin. Thus, RGM/neogenin is a novel dependence ligand/receptor couple as well as an axon guidance molecular complex. [source] Forked end: a novel transmembrane protein involved in neuromuscular specificity in drosophila identified by gain-of-function screeningDEVELOPMENTAL NEUROBIOLOGY, Issue 3 2002Takeshi Umemiya Abstract The Drosophila neuromuscular connectivity provides an excellent model system for studies on target recognition and selective synapse formation. To identify molecules involved in neuromuscular recognition, we conducted gain-of-function screening for genes whose forced expression in all muscles alters the target specificity. We report here the identification of a novel transmembrane protein, Forked end (FEND), encoded by the fend gene, by the said screening. When the FEND expression was induced in all muscles, motoneurons that normally innervate muscle 12 formed ectopic synapses on a neighboring muscle 13. The target specificity of these motoneurons was also altered in the loss-of-function mutant of fend. During embryonic development, fend mRNA was detected in a subset of cells in the central nervous system and in the periphery. These results suggest that FEND is a novel axon guidance molecule involved in neuromuscular specificity. © 2002 Wiley Periodicals, Inc. J Neurobiol 51: 205,214, 2002 [source] LIM-only protein 4 interacts directly with the repulsive guidance molecule A receptor NeogeninJOURNAL OF NEUROCHEMISTRY, Issue 2 2008Gregor Schaffar Abstract Repulsive guidance molecule A (RGM A) was recently described as a potent inhibitor of neuroregeneration in a rat spinal cord injury model. The receptor mediating RGM A's repulsive activity was shown to be Neogenin, a member of the Deleted in Colorectal Cancer (DCC) family of netrin receptors. Binding of RGM A to Neogenin induces activation of the small GTPase RhoA and of its effector Rho-kinase by an unknown mechanism. Here we show, that the cytoplasmic tail of Neogenin interacts directly with the transcriptional coactivator LIM domain only 4 (LMO4) in human SH-SY5Y cells, human Ntera neurons, and in embryonic rat cortical neurons. RGM A binding to Neogenin but not binding of Netrin-1, induces release of LMO4 from Neogenin. Down-regulation of LMO4 neutralizes the repulsive activity of RGM A in neuronal cell lines and embryonic rat cortical neurons and prevents RhoA activation. These results show for the first time that an interaction of Neogenin with LMO4 is involved in the RGM A , Neogenin signal transduction pathway for RhoA activation. [source] Myosin IIA is required for neurite outgrowth inhibition produced by repulsive guidance moleculeJOURNAL OF NEUROCHEMISTRY, Issue 1 2008Takekazu Kubo Abstract Although myelin-associated neurite outgrowth inhibitors express their effects through RhoA/Rho-kinase, the downstream targets of Rho-kinase remain unknown. We examined the involvement of myosin II, which is one of the downstream targets of Rho-kinase, by using blebbistatin , a specific myosin II inhibitor , and small interfering RNA targeting two myosin II isoforms, namely, MIIA and MIIB. We found that neurite outgrowth inhibition by repulsive guidance molecule (RGMa) was mediated via myosin II, particularly MIIA, in cerebellar granule neurons. RGMa induced myosin light chain (MLC) phosphorylation by a Rho-kinase-dependent mechanism. After spinal cord injury in rats, phosphorylated MLC in axons around the lesion site was up-regulated, and this effect depends on Rho-kinase activity. Further, RGMa-induced F-actin reduction in growth cones and growth cone collapse were mediated by MIIA. We conclude that Rho-kinase-dependent activation of MIIA via MLC phosphorylation induces F-actin reduction and growth cone collapse and the subsequent neurite retraction/outgrowth inhibition triggered by RGMa. [source] Repulsive guidance molecule/neogenin: a novel ligand-receptor system playing multiple roles in neural developmentDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 6 2004Eiji Matsunaga The repulsive guidance molecule (RGM) is a membrane-bound protein originally isolated as an axon guidance molecule in the visual system. Recently, the transmembrane protein, neogenin, has been identified as the RGM receptor. In vitro analysis with retinal explants showed that RGM repels temporal retinal axons and collapses their growth cones through neogenin-mediated signaling. However, RGM and neogenin are also broadly expressed at the early embryonic stage, suggesting that they do not only control the guidance of visual axons. Gene expression perturbation experiments in chick embryos showed that neogenin induces cell death, and its ligand, RGM, blocks the pro-apoptotic activity of neogenin. Thus, RGM/neogenin is a novel dependence ligand/receptor couple as well as an axon guidance molecular complex. [source] Delayed onset of midline netrin expression in Artemia franciscana coincides with commissural axon growth and provides evidence for homology of midline cells in distantly related arthropodsEVOLUTION AND DEVELOPMENT, Issue 2 2007Molly Duman-Scheel SUMMARY Although many similarities in arthropod central nervous systems (CNS) development exist, differences in midline cell formation and ventral nerve cord axonogenesis have been noted in arthropods. It is possible that changes in the expression of axon guidance molecules such as Netrin, which functions during commissural axon guidance in Drosophila and many other organisms, may parallel these differences. In this investigation, we analyze this hypothesis by examining Netrin accumulation during development of the brine shrimp Artemia franciscana, a branchiopod crustacean. An Artemia franciscana netrin (afrnet) orthologue was cloned. An antibody to the afrNet protein was generated and used to examine the pattern of afrNet accumulation during Artemia development. Despite differences between Drosophila and Artemia nerve cord development, examination of afrNet accumulation suggests that this protein functions to regulate commissure formation during Artemia CNS development. However, detection of afrNet at the midline and on commissural axons occurs at a relatively later time point in Artemia as compared with Drosophila. Detection of afrNet in a subset of midline cells that closely resemble Netrin-expressing cells at the Drosophila midline provides evidence for homology of midline cells in arthropods. Expression of Netrins in many other tissues is comparable, suggesting that Netrin proteins may play many conserved roles during arthropod development. [source] Semaphorin 3A and neurotrophins: a balance between apoptosis and survival signaling in embryonic DRG neuronsJOURNAL OF NEUROCHEMISTRY, Issue 2 2006Ayal Ben-Zvi Abstract Large numbers of neurons are eliminated by apoptosis during nervous system development. For instance, in the mouse dorsal root ganglion (DRG), the highest incidence of cell death occurs between embryonic days 12 and 14 (E12,E14). While the cause of cell death and its biological significance in the nervous system is not entirely understood, it is generally believed that limiting quantities of neurotrophins are responsible for neuronal death. Between E12 and E14, developing DRG neurons pass through tissues expressing high levels of axonal guidance molecules such as Semaphorin 3A (Sema3A) while navigating to their targets. Here, we demonstrate that Sema3A acts as a death-inducing molecule in neurotrophin-3 (NT-3)-, brain-derived neurotrophic factor (BDNF)- and nerve growth factor (NGF)-dependent E12 and E13 cultured DRG neurons. We show that Sema3A most probably induces cell death through activation of the c-Jun N-terminal kinase (JNK)/c-Jun signaling pathway, and that this cell death is blocked by a moderate increase in NGF concentration. Interestingly, increasing concentrations of other neurotrophic factors, such as NT-3 or BDNF, do not elicit similar effects. Our data suggest that the number of DRG neurons is determined by a fine balance between neurotrophins and Semaphorin 3A, and not only by neurotrophin levels. [source] Sema4D deficiency results in an increase in the number of oligodendrocytes in healthy and injured mouse brainsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 13 2009Yoshitaka Taniguchi Abstract Semaphorins, a family of secreted and membrane-bound proteins, are known to function as repulsive axon guidance molecules. Sema4D, a class 4 transmembrane-type semaphorin, is expressed by oligodendrocytes in the central nervous system, but its role is unknown. In this study, the effects of Sema4D deficiency on oligodendrocytes were studied in intact and ischemic brains of adult mice. As observed in previous studies, Sema4D marked by ,-galactosidase in Sema4D mutant mice was localized exclusively on myelin-associated glycoprotein (MAG)-positive oligodendrocytes but not on NG2-positive oligodendrocyte progenitor cells (OPCs). Although there was no difference in the number of the latter cells between Sema4D-deficient and wild-type mice, the number of MAG-positive cells was significantly increased in the cerebral cortex of both nonischemic and postischemic brains of Sema4D-deficient mice. Cell proliferation, observed by using bromodeoxyuridine incorporation, was evident in the MAG-positive cells that developed after cerebral ischemia. These data indicate that Sema4D is involved in oligodendrogenesis during development and during recovery from ischemic injury. © 2009 Wiley-Liss, Inc. [source] Spatially patterned gene expression for guided neurite extensionJOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2009Tiffany Houchin-Ray Abstract Axon pathfinding by localized expression of guidance molecules is critical for the proper development of the nervous system. In this report, we present a well-defined spatially patterned gene expression system to investigate neurite guidance in vitro. Nonviral gene delivery was patterned by combining substrate-mediated gene delivery with soft lithography techniques, and the amount of protein produced at the region of localized expression was varied by altering the vector concentration and the width of the pattern, highlighting the flexibility of the system. A neuronal coculture model was used to investigate responses to spatial patterns of nerve growth factor (NGF) expression. The soluble NGF gradient elicited a guidance cue, and the degree of guidance was governed by the distance a neuron was cultured from the pattern and the time between accessory cell and neuron seedings. A portion of the diffusible NGF bound to the culture surface in the extracellular space, and the surface-associated NGF supported neuron survival and neurite outgrowth. However, the surface-bound NGF gradient alone did not elicit a guidance signal, and in fact masked the guidance cue by soluble NGF gradients. Mathematical modeling of NGF diffusion was used to predict the concentration gradients, and both the absolute and fractional gradients capable of guiding neurites produced by patterned gene expression differed substantially from the values obtained with existing engineered protein gradients. Spatially patterned gene expression provides a versatile tool to investigate the factors that may promote neurite guidance. © 2008 Wiley-Liss, Inc. [source] Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 17JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2003M Scarlato The neuropilins, NP-1 and NP-2, are co-receptors for Sema3A and Sema3F, respectively, both of which are repulsive axonal guidance molecules. NP-1 and NP-2 are also co-receptors for vascular endothelial growth factor (VEGF). The neuropilins and their ligands are known to play prominent roles in axonal pathfinding, fasciculation, and blood vessel formation during peripheral nervous system (PNS) development. To screen for additional molecular mechanisms by which Schwann cells and fibroblasts contribute to successful PNS axonal regeneration, we used cDNA microarrays (Clontech) to compare expression profile of multiple messenger RNAs in sciatic nerves distal to transection with their levels in normal sciatic nerves. An evocative result of this screen was a 14-fold increase in NP-2 mRNA in the axotomized nerve segments 4 days post-transection. We verified that NP-2 is induced in transected as well as crushed nerve segments by quantitative PCR, Northern blotting, and Western blotting, and examined the distribution of NP-2 expressing cells in injured sciatic nerves by in situ hybridization. Then, we sought evidences of induction in the injured nerves of the NP-2 ligands, Sema3F and VEGF, and widened our survey to determine whether expression of the functionally related genes, neuropilin-1 (NP-1) and its class 3 semaphorin ligand, Sema3A are also induced in PNS following injury. We showed by in situ hybridization induction of all those genes at four days post-crushed, distally to the lesion. Our results suggest the possibility that the neuropilins and their semaphorin ligands serve to guide, rather than to impede, regenerating axons in the adult PNS. [source] Molecular determinants of the face map development in the trigeminal brainstemTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 2 2006Reha S. Erzurumlu Abstract The perception of external sensory information by the brain requires highly ordered synaptic connectivity between peripheral sensory neurons and their targets in the central nervous system. Since the discovery of the whisker-related barrel patterns in the mouse cortex, the trigeminal system has become a favorite model for study of how its connectivity and somatotopic maps are established during development. The trigeminal brainstem nuclei are the first CNS regions where whisker-specific neural patterns are set up by the trigeminal afferents that innervate the whiskers. In particular, barrelette patterns in the principal sensory nucleus of the trigeminal nerve provide the template for similar patterns in the face representation areas of the thalamus and subsequently in the primary somatosensory cortex. Here, we describe and review studies of neurotrophins, multiple axon guidance molecules, transcription factors, and glutamate receptors during early development of trigeminal connections between the whiskers and the brainstem that lead to emergence of patterned face maps. Studies from our laboratories and others' showed that developing trigeminal ganglion cells and their axons depend on a variety of molecular signals that cooperatively direct them to proper peripheral and central targets and sculpt their synaptic terminal fields into patterns that replicate the organization of the whiskers on the muzzle. Similar mechanisms may also be used by trigeminothalamic and thalamocortical projections in establishing patterned neural modules upstream from the trigeminal brainstem. © 2006 Wiley-Liss, Inc. [source] In vitro model for penetration of sensory nerve fibres on a Matrigel basement membrane: implications for possible application to intractable pruritusBRITISH JOURNAL OF DERMATOLOGY, Issue 5 2009M. Tominaga Summary Background, Epidermal hyperinnervation occurs in dermatoses with intractable pruritus, such as atopic dermatitis, suggesting that the hyperinnervation is partly responsible for abnormal itch perception. Objectives, To investigate the mechanisms of penetration of sensory nerve fibres into the basement membrane of the skin. Methods, A rat dorsal root ganglion neurone culture system consisting of Matrigel and a Boyden chamber containing a nerve growth factor (NGF) concentration gradient was used. In some experiments, matrix metalloproteinase (MMP) blockers and semaphorin 3A (Sema3A) were added to the culture system. Matrigel-coated membranes were stained with anti-Tau antibody, and the number of nerve fibres that crossed the membrane was counted. Expression of MMPs in the cultured neurones was examined at mRNA and protein levels by quantitative reverse transcription,polymerase chain reaction and immunocytochemistry, respectively. The activity was also examined by zymography. Results, Nerve fibres penetrated into Matrigel in the presence of an NGF concentration gradient, which was dose-dependently inhibited by GM6001, a broad-spectrum MMP inhibitor. Transcripts for MMP2, but not MMP9, were increased in the cultured neurones, and the penetration was dose-dependently inhibited by MMP-2 blockers. MMP-2 and its activity were partially localized on the NGF-responsive growth cones. NGF also upregulated pro-MMP-2 activation molecules in the cultured neurones. Sema3A stimulation showed the opposite effects on these NGF-dependent events. Interestingly, MMP2 expression was modulated by extracellular matrix (ECM) substrates for this enzyme. Conclusions, Membrane-associated MMP-2 contributes to penetration of nerve fibres into Matrigel through modulation by axonal guidance molecules and/or ECM. These findings provide insight for understanding the development of intractable pruritus involving epidermal nerve density. [source] | |||||||||||||