Multiple Signals Regulate Axon Regeneration Through the Nogo Receptor Complex

Abstract

Several myelin-derived proteins have been identified as components of central nervous system (CNS) myelin, which prevents axonal regeneration in the adult vertebrate CNS. The discovery of the receptor for these proteins was a major step toward understanding the failure of axon regeneration. The receptor complex consists of at least three elements: the p75 receptor (p75NTR), the Nogo receptor and LINGO-1. Downstream from the receptor complex, RhoA activation has been shown to be a key element of the signaling mechanism of these proteins. Rho activation arrests axon growth, and blocking Rho activation promotes axon regeneration in vivo. Recent studies have identified conventional protein kinase C as an additional necessary component for axon growth inhibition. Possible crosstalk downstream of these signals should be explored to clarify all the inhibitory signals and may provide an efficient molecular target against injuries to the CNS.

Nogo-A and Myelin-Associated Glycoprotein Differently Regulate Oligodendrocyte Maturation and Myelin Formation

“…Nogo-A binds to a multisubunit receptor complex including the Nogo66 receptor NgR1 (Fournier et al, 2001), the adaptor molecule Lingo-1 (Mi et al, 2004), and the effector components p75/Troy . The stimulation of this complex at the surface of neurons leads to the intracellular activation of the small GTPase RhoA that mediates actin depolymerization and thereby the collapse or retraction of neurites (Yamashita et al, 2005). The same molecular cascade can be elicited by MAG and oligodendrocyte myelin glycoprotein (OMgp), which are structurally different from Nogo-A but bind also to the NgR-p75 receptor complex (Wang et al, 2002a).…”

A Phase I/IIa Clinical Trial of a Recombinant Rho Protein Antagonist in Acute Spinal Cord Injury

“…The p75NTR portion of the receptor complex ( Fig. 1) signals directly to Rho, converting Rho to an activated state (Yamashita et al, 2002(Yamashita et al, , 2005. Chondroitin sulphate proteoglycans, inhibitory extracellular matrix molecules that are associated with the glial scar, have also been shown to act through the Rho signalling pathway to inhibit axon regeneration (Dergham et al, 2002, Monnier et al, 2003.…”

Mice lacking the p75 receptor fail to acquire a normal complement of taste buds and geniculate ganglion neurons by adulthood

“…For example, the p75 receptor has been shown to enhance neuron survival in some instances (Stucky and Koltzenburg, 1997;DeFreitas et al, 2001;Song and Posse de Chaves, 2003) and to mediate cell death in others (Agerman et al, 2000;Botchkarev et al, 2000;Lee et al, 2001;Troy et al, 2002). Axon growth (Yamashita et al, 1999;Bentley and Lee, 2000;Gallo and Letourneau, 2004;Gehler et al, 2004) and axonal regeneration (Boyd and Gordon, 2001;Song et al, 2004Song et al, , 2005Yamashita et al, 2005b) are also differentially regulated by this receptor.…”