Victims of traumatic spinal cord injury often learn that it's not possible to repair their 'broken backs' and are faced with the prospect of paralysis; the injured axons of central neurons are disconnected from their targets in the spinal cord. But these axons do try to repair themselves: their tips actually reseal, re-form a growth cone and attempt to regenerate a new axon segment. In fact, lesions of peripheral axons can actually be repaired. However, the problem in the central nervous system is that there are molecules that suppress this regenerating capacity.

A protein called Nogo, whose gene was first cloned at the beginning of last year, seems to be one such inhibitory molecule. Nogo-A — the full-length version — is highly abundant in myelin produced by oligodendrocytes in the central nervous system, but not in peripheral myelin produced by Schwann cells. Nogo-A has two transmembrane domains, and the only part of the protein that is exposed to the extracellular surface is a 66-amino-acid linker termed Nogo-66. It has been argued that the cytoplasmic region of Nogo-A is the part of the molecule that inhibits axon regeneration at sites of oligodendrocyte injury. However, a role for Nogo-66 has not been ruled out. Does the extracellular domain of Nogo also have inhibitory activity?

In a recent report in Nature, Fournier et al. reveal important information that might help to answer this and other questions on the role of Nogo in the regeneration puzzle. The authors explored what functional domains of the protein are responsible for the inhibitory activity. They showed that Nogo-66 inhibits axon growth but does not alter cell morphology. By contrast, the cytoplasmic domain of Nogo does affect the morphology of neurons and other cell types. The authors come down in favour of Nogo-66 as the axonal-regeneration-inhibiting activity and argue that the cytosolic domain of Nogo does not act directly on the neurons but, instead, modifies their substrate. Furthermore, Fournier et al. cloned a receptor for Nogo-66 and showed that it is a glycosylphosphatidylinositol-anchored protein capable of mediating inhibition of axon regeneration. The receptor is expressed in the central grey matter; more specifically, in neurons known to regenerate in the presence of antibodies against Nogo.

The identification of the Nogo-66 receptor has implications for our understanding of the basic mechanisms of neural regeneration and plasticity, and will no doubt raise the possibility of therapeutic applications. Perhaps disrupting the interaction of Nogo-66 with its receptor might help to promote axonal regeneration after spinal cord damage or other forms of traumatic injury. Clearly, this possibility will depend on formal evidence that Nogo can actually inhibit axonal regeneration in vivo, a piece of the puzzle so far unsolved.