What prevents axons from regenerating across the DREZ? The prevailing view in the field is that regeneration is prevented at the DREZ primarily by growth-inhibiting activities associated with reactive astrocytes and/or degenerating oligodendrocytes. Because axons contact astrocytes when they have stopped regeneration at the DREZ [40
], reactive astrocytes are thought to form the primary regenerative barrier. Consistent with this notion, axons grow through the DREZ that has been depleted of astrocytes by X-irradiation [43
], and, in general, (despite exceptions [6
]), reactive astrocytes inhibit neurite outgrowth [8
] by producing chondroitin sulfate proteoglycans (CSPGs) that collapse or repel neurite outgrowth [46
]. Members of the CSPG family of extracellular matrix molecules include neuroglycan 2 (NG2), aggrecan, brevican, neurocan, vesican and phosphacan [45
]. These CSPGs are expressed at the DREZ both during development and after dorsal root injury [48
The differential expression and contribution of individual members of the CSPG family have also been studied. NG2, the most important component, is a major inhibitory proteoglycan for sensory axons [49
]. NG2 is expressed by oligodendrocyte progenitor cells, which react rapidly following CNS injury, and by some reactive astrocytes. Virus-mediated knockdown or antibody blocking of NG2 promotes intraspinal sensory axon regeneration [50
]. Recently, a transmembrane protein tyrosine phosphatase, PTPσ, was identified as a high affinity receptor of CSPG that mediates its inhibitory effect [51
]. Disruption of the PTPσ gene reduced inhibition by CSPG.
Several lines of evidence argue that astrocytes and CSPGs are not the critical determinant of regeneration failure. For example, the same CSPGs are expressed abundantly in tissue that supports regeneration (dorsal roots) and in tissue in which regeneration fails (DREZ and spinal cord) [53
]. The inhibitory properties of CSPGs are primarily due to glycosaminoglycan (GAG) side chains; enzymatic removal of GAG chains by chondroitinase ABC (ChABC) promotes intraspinal axon regeneration [46
]. However, pharmacological degradation of CSPGs by chondroitinase ABC or Phosphatidylinositol-specific phospholipase C (Pi-PLC), which enhances regeneration in the damaged spinal cord [55
], does not promote regeneration across the DREZ [23
; but see Cafferty et al., 2007]. How astrocytes prevent regeneration, if they indeed play a crucial role in the regeneration failure, remains uncertain.