Myelin-, reactive glia-, and scar-derived CNS axon growth inhibitors: expression, receptor signaling, and correlation with axon regeneration.
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.
Sandvig
Axel
A
Laboratory of Regenerative Neurobiology, Institute for Experimental Medical Research, Ullevål University Hospital, Oslo, Norway. axel.sandvig@ioks.uio.no
Berry
Martin
M
Barrett
Lee B
LB
Butt
Arthur
A
Logan
Ann
A
D000818:Animals; D001369:Axons / Q000502:physiology*; D002921:Cicatrix / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000502:physiology; D006131:Growth Inhibitors / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D009186:Myelin Sheath / Q000502:physiology*; D009416:Nerve Regeneration / Q000502:physiology*; D009457:Neuroglia / Q000502:physiology*; D017475:Receptors, Nerve Growth Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D006131:Growth Inhibitors; D017475:Receptors, Nerve Growth Factor