Myelin‐, reactive glia‐, and scar‐derived CNS axon growth inhibitors: Expression, receptor signaling, and correlation with axon regeneration

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/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.

Degradation of Chondroitin Sulfate Proteoglycans Induces Sprouting of Intact Purkinje Axons in the Cerebellum of the Adult Rat

“…Although the growth phenomena observed in these two experimental conditions can be related to common underlying mechanisms (i.e., the removal of environmental inhibitory cues), which likely share common signaling pathways (Sandvig et al, 2004), some distinctive features characterize the axonal plasticity induced by ChABC application. First, in the present material, we failed to detect the thickened axon segments budding several short sprouts, which were frequently encountered after antiNogo injection (Buffo et al, 2000).…”

Exercise decreases myelin‐associated glycoprotein expression in the spinal cord and positively modulates neuronal growth

“…To a large extent, the failure of CNS axons to regenerate is the result of a nonpermissive environment that includes multiple factors such as formation of glial scar, deficiency in trophic factors and growth-inhibitors produced by oligodendrocytes, reactive astrocytes and fibroblasts (Domeniconi and Filbin, 2005;Fawcett and Asher, 1999;Filbin, 2003;Gage, 2000, 2002;McGee and Strittmatter, 2003;Sandvig et al, 2004;Silver and Miller, 2004). Recently, myelin-derived growth-inhibitory signals have been shown to play a major role in hampering axonal growth across the site of injury (Liebscher et al, 2005;Merkler et al, 2001).…”

Selective temporal and regional alterations of Nogo-A and small proline-rich repeat protein 1A (SPRR1A) but not Nogo-66 receptor (NgR) occur following traumatic brain injury in the rat

“…These and other studies revealed that inhibitors of axonal outgrowth, present in myelin, are among the possible factors underlying the abortive regeneration of mature CNS neurons observed following CNS injury (Huang et al, 1999;Grados-Munro and Fournier, 2003). The importance of myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp) and Nogo-A in CNS injury has been addressed in several recent reviews, due to their proposed role of inhibiting axonal outgrowth (Hunt et al, 2002a;David and Lacroix, 2003;Sandvig et al, 2005;Schwab, 2004).…”