Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

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

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.
...
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.
...
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.
...
PMID:Nogo-A and myelin-associated glycoprotein mediate neurite growth inhibition by antagonistic regulation of RhoA and Rac1. 1245 Nov 36

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.
...
PMID:The Nogo receptor, its ligands and axonal regeneration in the spinal cord; a review. 1281 33

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.
...
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.
...
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.
...
PMID:Oligodendrocyte myelin glycoprotein (OMgp): evolution, structure and function. 1514 22

When associated with the Nogo receptor (NgR), the transmembrane receptor p75NTR signals growth cone collapse. Arrest of CNS axon growth in vivo is mediated by CNS myelin-derived inhibitory ligands through either an unknown pathway after NgR- and Ca2+-dependent activation of the epidermal growth factor receptor (EGFR), and/or sequential Rho-A/ROCK/LIM-kinase/cofilin phosphorylation leading to actin depolymerization. Paradoxically, rat retinal ganglion cell (RGC) axons regenerate through the CNS myelin-rich transected optic nerve after intravitreal sciatic nerve grafting without inhibitory ligand neutralization. Here, we show that optic nerve regeneration in vivo correlates with Schwann cell-derived factor-induced cleavage of NgR and Nogo-A, and inactivation of p75NTR signalling by the induction of regulated intramembranous proteolysis (RIP) and the release of both extracellular (p75ECD) and intracellular (p75ICD) domains. Hence, Schwann cell-derived factors compromise inhibitory signalling by (i) antagonizing ligand/NgR binding with metalloproteinase-cleaved Nogo-A peptides; (ii) RIP of p75NTR; (iii) competitively blocking NgR/p75NTR clustering with soluble p75ECD; and (iv) consequent reduced downstream EGFR phosphorylation and suppression of Rho-A activation. Moreover, in RGC cultures, exogenous tumour necrosis- converting enzyme (TACE) initiates RIP of p75NTR, reduces EGFR phosphorylation, suppresses activation of Rho-A, cleaves the ECD from both NgR and TROY, and disinhibits neurotrophic factor (NTF) stimulated RGC neurite outgrowth in the presence of CNS myelin. Soluble NgRECD binds all CNS myelin-derived ligands and thus has the potential to act as an inhibitory signalling antagonist, but the role of TROY and its shed ectodomain in growth cone mobility is unknown. siRNA knockdown of p75NTR also inactivates Rho-A and disinhibits NTF-stimulated RGC neurite outgrowth in cultures with added CNS myelin. In all the above experimental paradigms, Schwann cell-derived factor/NTF-induced attenuation of NgR/p75NTR signalling suppresses EGFR activation, thereby potentiating axon growth disinhibition.
...
PMID:Schwann cell-derived factor-induced modulation of the NgR/p75NTR/EGFR axis disinhibits axon growth through CNS myelin in vivo and in vitro. 1661 94

Rho family proteins can coordinate multiple signaling pathways through their ability to regulate both gene transcription and the actin cytoskeleton. With respect to the neuronal Nogo receptor (NgR), recent data assign a key role for the GTPase Rho in the control of cellular responses leading to actin cytoskeletal rearrangements and finally resulting in axonal outgrowth inhibition and growth cone collapse in the adult human central nervous system. In order to evaluate potential NgR antagonists, human embryonic kidney 293 cells stably overexpressing RhoA in the absence or presence of NgR have been generated. RhoA activation induced by stimulation with the alkaline phosphatase-tagged NgR ligand Nogo66 (AP-Nogo66) was confirmed by affinity-precipitation of the GTPase with the Rho-binding domain from Rhotekin. As this pull-down assay is not applicable to a higher-throughput format, a cellular Rho GTPase activation assay strategy based on the ability of Rho to regulate the actin cytoskeleton was developed. Stimulation with L-alpha-lysophosphatidic acid (LPA), a Rho activator acting through the ubiquitiously expressed LPA receptors, induced significant cytoskeletal rearrangement resulting in cell contraction in all RhoA-overexpressing cell lines. In contrast, stimulation with AP-Nogo66 resulted in Rho-dependent cell contraction with a similar time course only in the NgR-expressing cell line. Moreover, the NgR-induced Rho-dependent morphological changes could be analyzed and quantified with customary image analysis software. In conclusion, the cytoskeletal rearrangement assay is amenable to automated high-content screening and has the potential to eliminate major technical bottlenecks of the pull-down assay. The increased throughput of the cellular GTPase activation assay compared with the biochemical method should facilitate the evaluation of compounds that modulate the actin cytoskeleton through Rho.
...
PMID:A high-content screening assay for the Nogo receptor based on cellular Rho activation. 1671 17

After binding, central nervous system (CNS) myelin-derived axon growth inhibitory ligands, the Nogo-66 receptor (NgR), complexes with LINGO-1 and either the low-affinity neurotrophin receptor (p75(NTR)) or TROY to initiate growth cone collapse via a Rho-A inhibitory signaling pathway and/or Ca(2+)-dependent activation of epidermal growth factor receptor (EGFR) through an unknown signaling pathway. We have shown that axon growth through CNS myelin is disinhibited after neurotrophic factor administration by 1) initiating intramembranous proteolysis (RIP) of p75(NTR), leading to cleavage of the extracellular (p75(ECD)) and intracellular domains (p75(ICD)) by alpha- and gamma-secretase, respectively, thereby paralyzing inhibitory signaling; 2) shedding of soluble NgR(ECD), which acts as a competitive antagonist to NgR for binding of inhibitory ligands; and 3) antagonizing NgR/p75(NTR) clustering by competitive p75(ECD)/NgR interaction. Here, we report that TNF-alpha converting enzyme (TACE) (a disintegrin and metalloproteinase 17, ADAM17) induces disinhibition of FGF2-stimulated neurite outgrowth of dorsal root ganglion neurons (DRGN) cultured in the presence of a predetermined concentration of inhibitory CNS myelin-derived ligands. After addition of TACE (which has alpha-secretase activity) to mitotically arrested adult rat mixed DRG cultures, we demonstrate 1) NgR(ECD) shedding; 2) release of p75(ECD) and p75(ICD) by RIP of p75(NTR); 3) blockade of Rho-A activation; 4) reduced EGFR phosphorylation; and 5) increased FGF2-stimulated DRGN neurite outgrowth and branching in the presence of CNS myelin-derived inhibitory ligands. Thus, TACE-induced cleavage of NgR and RIP of p75(NTR) abrogates axon growth inhibitory signaling, thereby disinhibiting CNS axon/neurite growth.
...
PMID:TACE-induced cleavage of NgR and p75NTR in dorsal root ganglion cultures disinhibits outgrowth and promotes branching of neurites in the presence of inhibitory CNS myelin. 1684 93


1 2 3 4 Next >>

---