Nogo domains and a Nogo receptor: implications for axon regeneration.

The identification of Nogo and NgR represent important advances in understanding axon inhibition by CNS myelin and provide a new molecular basis to study regeneration. In vivo gain- and loss-of-function studies, including gene targeting, of Nogo isoforms and NgR will be critical to unravel their functions. In addition to testing effects on recovery from injury, it will be fascinating to investigate the normal function of Nogo, which has been speculated to prevent excessive neural plasticity in the adult CNS.The relative contributions to regenerative failure of the glial scar versus myelin inhibitors has been a long-standing subject of debate (see Figure 1Figure 1). On the one hand, it is clear that IN-1 antibody can block myelin inhibitory activities in culture and can promote recovery in lesioned animals. Moreover, impressive regeneration of up to 50% of corticospinal fibers was recently reported by David and colleagues in a novel approach involving vaccination of mice with myelin (Huang et al., 1999xHuang, D.W, McKerracher, L, Braun, P.E, and David, S. Neuron. 1999; 24: 639–647Abstract | Full Text | Full Text PDF | PubMedSee all References(Huang et al., 1999). These studies suggest a key role for myelin inhibitors of regeneration. On the other hand, elegant experiments by Silver and colleagues have shown that when adult neurons are carefully microtransplanted without creating a glial scar, their axons can regenerate long distances over heavily myelinated adult CNS tracts. Although it might be argued that the transplanted axons did not come in contact with the inhibitory inner myelin leaflet, they can even grow through areas of Wallerian degeneration and stall only after encountering a gliotic barrier. These results suggest that general myelin inhibitors may not be as potent in preventing regeneration as previously thought (Davies et al. 1997xDavies, S.J.A, Fitch, M.T, Memberg, S.P, Hall, A.K, Raisman, G, and Silver, J. Nature. 1997; 390: 680–683PubMedSee all References, Davies et al. 1999xDavies, S.J.A, Goucher, D.R, Doller, C, and Silver, J. J. Neurosci. 1999; 19: 5810–5822PubMedSee all References, and references therein). Although these various studies may initially seem contradictory, one possibility is that rather than promoting only direct regeneration of damaged pathways, neutralization of myelin inhibitors may promote functional recovery by freeing up CNS plasticity and thus allowing formation of new pathways that can compensate for the lost ones (Figure 1CFigure 1C; Z'Graggen et al., 2000xZ'Graggen, W.J, Fouad, K, Raineteau, O, Metz, G.A.S, Schwab, M.E, and Kartje, G.L. J. Neurosci. 2000; 20: 6561–6569PubMedSee all ReferencesZ'Graggen et al., 2000). Alternatively, the studies might be reconciled if some of the same molecules are general myelin inhibitors and also glial scar inhibitors. The new molecular tools should help answer these questions.Moving toward therapeutic approaches for CNS injury is a complex challenge. In addition to the known inhibitory components, molecules initially identified as developmental guidance factors such as semaphorins, ephrins, netrins, and slits probably play a role in the adult CNS. Especially considering the large number of candidate inhibitors, rather than blocking them extracellularly, it may ultimately be more effective to modulate intracellular pathways of axon responsiveness. Successful regeneration depends on additional factors such as survival of injured neurons and establishment of functional connections. On the positive side, even limited functional improvement may be valuable clinically. While even this is likely to take years, the new molecular studies give grounds for cautious hope. We may at last be in an era when CNS injury will become an ailment to be treated.