Nogo and Nogo-66 receptor in human and chick: implications for development and regeneration

Antibodies to the myelin protein Nogo increase axonal regrowth after central nervous system injury. We have investigated whether Nogo expression contributes to loss of regenerative potential during development by using chick embryos, which regenerate their spinal cord until embryonic day (E) 13, when myelination begins. We show that Nogo-A and the Nogo receptor (NgR) are developmentally regulated both in chick and human embryos, are first detected at developmental stages when the chick spinal cord regenerates, and are not down-regulated after injury at permissive stages for regeneration. Therefore, expression of Nogo-A and NgR in pre-E13 chick spinal cords is not sufficient to inhibit regeneration. Nogo-A expression in the chick early embryo is primarily observed in axons, whereas NgR is mainly located on neuronal cell bodies, both in spinal cord and eye, and in striated muscle including the heart. With the onset of myelination, there is down-regulation of Nogo-A expression in neurons. Therefore, loss of regenerative potential might be linked to changes in its cellular localization. The possibility that only Nogo expressed in mature oligodendrocytes can exercise inhibitory effects would reconcile the lack of inhibition we observe in developing chick spinal cords before the onset of myelination with evidence from other laboratories on the inhibitory effects of Nogo in mature central nervous system. The distinctive and complementary patterns of Nogo-A and NgR expression and their conservation throughout evolution support the view that Nogo signaling represents a key pathway in nervous system and striated muscle development. Its putative role in target innervation and establishment of neural circuitry is discussed.