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Query: UMLS:C0344329 (collapse)
 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The lack of regrowth of injured neurons in the adult central nervous system (CNS) of higher vertebrates was accepted as a fact for many decades. In the last few years a very different view emerged; regeneration of lesioned fibre tracts in vivo could be induced experimentally, and molecules that are responsible for inhibition and repulsion of growing neurites have been defined. Mechanisms that link cellular phenomena like growth cone turning or growth cone collapse to intracellular changes in second messenger systems and cytoskeletal dynamics became unveiled. This article reviews recent developments in this field, focusing especially on one of the best characterised neurite out-growth inhibitory molecules found in CNS myelin that was recently cloned: Nogo-A. Nogo-A is a high molecular weight transmembrane protein and an antigen of the monoclonal antibody mAb IN-1 that was shown to promote long-distance regeneration and functional recovery in vivo when applied to spinal cord-injured adult rats. Nogo-A is expressed by oligodendrocytes in white matter of the CNS. With the molecular characterisation of this factor new possibilities open up to achieve structural and functional repair of the injured CNS.
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PMID:Nogo-A, a potent inhibitor of neurite outgrowth and regeneration. 1093 71

The recently cloned gene Nogo, whose alternative splice products correspond to the antigenic target of the central nervous system (CNS) regeneration enhancing monoclonal antibody IN-1, codes for membrane proteins enriched in brain, particularly in oligodendrocytes. The 66-amino acid extracellular domain of Nogo (Nogo-66) interacts with a high-affinity receptor (NgR), a glycosylphosphatidylinositol (GPI)-linked protein with multiple leucine-rich repeats. The amino terminal cytoplasmic domain of Nogo appears to have a general cellular growth inhibitory effect. Nogo-66, on the other hand, specifically retards neurite outgrowth and induces growth cone collapse, possibly through its interaction with NgR and as yet unidentified transmembrane coreceptors. Recent results also suggest that Nogo expression may induce apoptosis in tumor cells. Together, these proteins provide new molecular handles for the design of therapeutic interventions for CNS injuries and neurodegenerative diseases, as well as possible leads to anticancer strategies.
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PMID:Nogos and the Nogo-66 receptor: factors inhibiting CNS neuron regeneration. 1189 68

Axonal regeneration in the adult central nervous system (CNS) is limited by two proteins in myelin, Nogo and myelin-associated glycoprotein (MAG). The receptor for Nogo (NgR) has been identified as an axonal glycosyl-phosphatidyl-inositol (GPI)-anchored protein, whereas the MAG receptor has remained elusive. Here, we show that MAG binds directly, with high affinity, to NgR. Cleavage of GPI-linked proteins from axons protects growth cones from MAG-induced collapse, and dominant-negative NgR eliminates MAG inhibition of neurite outgrowth. MAG-resistant embryonic neurons are rendered MAG-sensitive by expression of NgR. MAG and Nogo-66 activate NgR independently and serve as redundant NgR ligands that may limit axonal regeneration after CNS injury.
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PMID:Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor. 1218 16

The adult mammalian CNS has a limited capacity for nerve regeneration and structural plasticity. The presence of glia-derived inhibitory factors myelin-associated glycoprotein (MAG) and Nogo-A have been suggested to provide a nonpermissive environment for elongating nerve fibers. In particular, Nogo-A, an integral membrane protein predominantly expressed by oligodendrocytes, has been demonstrated to impair neurite growth in vitro and in vivo. Structure function analysis revealed that Nogo-A protein contains at least two active domains, NiG and Nogo-66, with diverse effects on neurite outgrowth and cell spreading. We now provide evidence that these inhibitory domains mediate their effects via an antagonistic regulation of the small GTPases RhoA and Rac1, resulting in activation of RhoA and suppression of Rac1. By inactivating RhoA with C3 transferase or the downstream effector Rho-kinase ROCK with, the inhibitory effects of both Nogo-A fragments and MAG on neurite outgrowth and oligodendrocyte-mediated growth cone collapse were abolished. Furthermore, we show that the recently cloned receptor for Nogo-66 and MAG, NgR, is not necessary for either NiG- or MAG-induced RhoA activation.
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PMID:Nogo-A and myelin-associated glycoprotein mediate neurite growth inhibition by antagonistic regulation of RhoA and Rac1. 1245 Nov 36

Nogo-A, a reticulon protein expressed by oligodendrocytes, contributes to the axonal growth inhibitory action of central myelin in growth cone collapse and neurite outgrowth in vitro assays, and antibody and inhibitor studies have implicated a role for Nogo in regeneration in the adult CNS in vivo. Three independent labs have now produced Nogo knockout mice with, quite unexpectedly, three different regeneration phenotypes.
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PMID:No Nogo: now where to go? 1271 56

At least three proteins present in CNS myelin, Nogo, MAG and OMgp are capable of causing growth cone collapse and inhibiting neurite outgrowth in vitro. Surprisingly, Nogo and OMgp are also strongly expressed by many neurons (including neocortical projection cells). Nogo expression is increased by some cells at the borders of CNS lesion sites and by cells in injured peripheral nerves, but Nogo and CNS myelin are largely absent from spinal cord injury sites, which are none the less strongly inhibitory to axonal regeneration. Nogo is found on growing axons during development, suggesting possible functions for neuronal Nogo in axon guidance. Although Nogo, MAG and OMgp lack sequence homologies, they all bind to the Nogo receptor (NgR), a GPI-linked cell surface molecule which, in turn, binds p75 to activate RhoA. NgR is strongly expressed by cerebral cortical neurons but many other neurons express NgR weakly or not at all. Some neurons, such as DRG cells, respond to Nogo and CNS myelin in vitro although they express little or no NgR in vivo which, with other data, indicates that other receptors are available for NgR ligands. NgR expression is unaffected by injury to the nervous system, and there is no clear correlation between NgR expression by neurons and lack of regenerative ability. In the injured spinal cord, interactions between NgR and its ligands are most likely to be important for limiting regeneration of corticospinal and some other descending tracts; other receptors may be more important for ascending tracts. Antibodies to Nogo, mainly the poorly-characterised IN-1 or its derivatives, have been shown to enhance recovery from partial transections of the spinal cord. They induce considerable plasticity from the axons of corticospinal neurons, including sprouting across the midline and, to a limited extent, regeneration around the lesion. Regeneration of corticospinal axons induced by Nogo antibodies has not yet been demonstrated after complete transections or contusion injuries of the spinal cord. It is not clear whether antibodies against Nogo act on oligodendrocytes/myelin or by binding to neuronal Nogo, or whether they can stimulate regeneration of ascending axons in the spinal cord, most of which express little or no NgR. Despite these uncertainties, however, NgR and its ligands offer important new targets for enhancing plasticity and regeneration in the nervous system.
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PMID:The Nogo receptor, its ligands and axonal regeneration in the spinal cord; a review. 1281 33

Nogo-A is a potent neurite growth inhibitor in vitro and plays a role both in the restriction of axonal regeneration after injury and in structural plasticity in the CNS of higher vertebrates. The regions that mediate inhibition and the topology of the molecule in the plasma membrane have to be defined. Here we demonstrate the presence of three different active sites: (1) an N-terminal region involved in the inhibition of fibroblast spreading, (2) a stretch encoded by the Nogo-A-specific exon that restricts neurite outgrowth and cell spreading and induces growth cone collapse, and (3) a C-terminal region (Nogo-66) with growth cone collapsing function. We show that Nogo-A-specific active fragments bind to the cell surface of responsive cells and to rat brain cortical membranes, suggesting the existence of specific binding partners or receptors. Several antibodies against different epitopes on the Nogo-A-specific part of the protein as well as antisera against the 66 aa loop in the C-terminus stain the cell surface of living cultured oligodendrocytes. Nogo-A is also labeled by nonmembrane-permeable biotin derivatives applied to living oligodendrocyte cultures. Immunofluorescent staining of intracellular, endoplasmic reticulum-associated Nogo-A in cells after selective permeabilization of the plasma membrane reveals that the epitopes of Nogo-A, shown to be accessible at the cell surface, are exposed to the cytoplasm. This suggests that Nogo-A could have a second membrane topology. The two proposed topological variants may have different intracellular as well as extracellular functions.
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PMID:Nogo-A inhibits neurite outgrowth and cell spreading with three discrete regions. 1284 38

The neurotrophin receptor p75NTR is the coreceptor for Nogo receptor, mediating growth cone collapse in vitro by MAG, myelin oligodendrocyte glycoprotein (Omgp), and Nogo. Whether p75NTR plays any role in the failure of nerve regeneration in vivo is not known. Immunohistochemical data showed that p75NTR was expressed in only a very small subset of ascending sensory axons but not in any corticospinal axons in the dorsal column of either normal or injured spinal cord. Using p75NTR-deficient mice, we showed that the depletion of the functional p75NTR did not promote the regeneration of the descending corticospinal tract and ascending sensory neurons in the spinal cord 2 weeks after spinal cord injury. Local administration of p75NTR-Fc fusion molecule, the dominant-negative receptor to block the function of neurite outgrowth inhibitors, did not improve regeneration of ascending sensory neurons in the injured spinal cord. Our results suggest that p75NTR may not be a critical molecule mediating the function of myelin-associated inhibitory factors in vivo.
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PMID:Suppression of p75NTR does not promote regeneration of injured spinal cord in mice. 1472 54

Axon regeneration is arrested in the injured central nervous system (CNS) by axon growth-inhibitory ligands expressed in oligodendrocytes/myelin, NG2-glia, and reactive astrocytes in the lesion and degenerating tracts, and by fibroblasts in scar tissue. Growth cone receptors (Rc) bind inhibitory ligands, activating a Rho-family GTPase intracellular signaling pathway that disrupts the actin cytoskeleton inducing growth cone collapse/repulsion. The known inhibitory ligands include the chondroitin sulfate proteoglycans (CSPG) Neurocan, Brevican, Phosphacan, Tenascin, and NG2, as either membrane-bound or secreted molecules; Ephrins expressed on astrocyte/fibroblast membranes; the myelin/oligodendrocyte-derived growth inhibitors Nogo, MAG, and OMgp; and membrane-bound semaphorins (Sema) produced by meningeal fibroblasts invading the scar. No definitive CSPG Rc have been identified, although intracellular signaling through the Rho family of G-proteins is probably common to all the inhibitory ligands. Ephrins bind to signalling Ephs. The ligand-binding Rc for all the myelin inhibitors is NgR and requires p75(NTR) for transmembrane signaling. The neuropilin (NP)/plexin (Plex) Rc complex binds Sema. Strategies for promoting axon growth after CNS injury are thwarted by the plethora of inhibitory ligands and the ligand promiscuity of some of their Rc. There is also paradoxical reciprocal expression of many of the inhibitory ligands/Rc in normal and damaged neurons, and NgR expression is restricted to a limited number of neuronal populations. All these factors, together with an incomplete understanding of the normal functions of many of these molecules in the intact CNS, presently confound interpretive acumen in regenerative studies.
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PMID:Myelin-, reactive glia-, and scar-derived CNS axon growth inhibitors: expression, receptor signaling, and correlation with axon regeneration. 1504 47

The oligodendrocyte myelin glycoprotein (OMgp) is a glycosylphosphatidylinositol-anchored protein expressed by neurons and oligodendrocytes in the central nervous system (CNS). Although the precise function of OMgp is yet to be determined in vivo, recent in vitro studies suggested roles for this protein in both the developing and adult central nervous system. In vitro experiments demonstrated the participation of OMgp in growth cone collapse and inhibition of neurite outgrowth through its interaction with NgR, the receptor for Nogo. This function requires its leucine-rich repeat domain, a highly conserved region in OMgp during mammal evolution. OMgp leucine-rich repeat domain is also implicated in the inhibition of cell proliferation. Based on its developmental expression, localization and structure, OMgp may also be involved in the formation and maintenance of myelin sheaths. Cell proliferation, neuronal sprouting and myelination are crucial processes involved in brain development and regeneration after injury. Here, we review the information available on the structure and evolution of OMgp, summarize its tissue expression and discuss its putative role(s) during the development and in adult CNS.
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PMID:Oligodendrocyte myelin glycoprotein (OMgp): evolution, structure and function. 1514 22


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