Meylin-, reactive glia-, and scar-derived CNS axon growth inhibitors: expression, receptor signaling, and correlation with axon regeneration

Research output: Contribution to journalReview article

Authors

Colleges, School and Institutes

Abstract

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/fibro-blast 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. (C) 2004 Wiley-Liss, Inc.

Details

Original languageEnglish
Pages (from-to)225-251
Number of pages27
JournalGLIA
Volume46
Issue number3
Publication statusPublished - 1 Jan 2004

Keywords

  • Brevican, Nogo receptor, protein kinase A, Versican, axon growth inhibitors, oligodendrocytes, extracellular matrix molecules, Nogo, NG2 chondroitin sulfate proteoglycans, RhoA, oligodendrocyte myelin glycoprotein, ephrin/Eph, meningeal fibroblasts, NG2-glia, Rac, axon regeneration, neuropilin, Rho-family GTPases, Cdc42, collapsin response mediator protein, Tenascin, p75 (NTR), chondroitin sulfate proteoglycans, Phosphacan, Neurocan, growth cone collapse, astrocytes, semaphorins, CNS scar, myelin-associated glycoprotein