White matter inhibitors in CNS axon regeneration failure - PubMed (original) (raw)

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White matter inhibitors in CNS axon regeneration failure

Fang Xie et al. Exp Neurol. 2008 Feb.

Abstract

Multiple lines of evidence have indicated that the inability of adult mammalian central nervous system (CNS) axons to regenerate after injury is partly due to the growth inhibitory property of central myelin. Three prototypical myelin-associated inhibitors of neurite outgrowth have been identified, including Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein (OMgp). These inhibitory ligands, their receptors and signaling pathways are being intensively investigated for their roles in CNS axon regeneration failure. In addition, several members of the axon guidance molecules have been implicated in restricting CNS axon regeneration, some of which are expressed by mature oligodendrocytes. Here we review in vitro and in vivo studies of these molecules in neurite growth and in axon regeneration failure and discuss the implications of these studies. While the increasing number of potential axon regeneration inhibitors highlights the complexity of the restrictive CNS environment, it provides new windows of opportunity as well as new challenges for therapeutic development for spinal cord injury and related neurological conditions.

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Figure 1

Figure 1

The prototypical myelin-derived neurite growth inhibitors, their receptors and intracellular signaling pathway. Oligodendrocyte-expressed Nogo, MAG, and OMgp all bind to GPI-anchored protein NgR1, which recruits co-receptor p75 or TROY and LINGO-1 to form a receptor complex to transduce the inhibitory signals in neurons. MAG also binds to NgR2, where the identity of co-receptors has not been confirmed. In neurons, the NgR1 receptor complex stimulates the dissociation of Rho-GDP from GDI and the subsequent formation of active Rho-GTP, which with additional downstream effectors leads to rearrangement of cytoskeletons to inhibit neurite outgrowth. Other downstream effectors for axon growth inhibition include PKC and EGFR, which are related to calcium influx. However, cAMP/PKA plays an opposite role by relieving the growth inhibition.

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