Nogo and myelin-associated glycoprotein (MAG) — two myelin proteins that limit axon regeneration — have received attention as possible therapeutic targets after spinal cord injury. The action of Nogo depends on its axonal receptor, NgR. By contrast, the identity of the MAG receptor has remained a mystery. Now Liu et al. and Domeniconi et al. report that MAG also binds to NgR, and that this interaction mediates its inhibitory effect on axon outgrowth.

Both studies show that MAG and NgR interact directly and that disrupting this interaction prevents MAG from inhibiting axonal growth. In addition, Liu et al. found that expressing NgR conferred MAG sensitivity on otherwise insensitive neurons.

Although the findings from both groups agree in general, they differ in one important respect; whereas Domeniconi et al. found that Nogo and MAG compete for the same site on NgR, Liu et al. obtained evidence for independent binding sites. It will be important to resolve this difference, as the existence of more than one binding site might have implications for the design of molecules that aim to block the inhibitory action of NgR.

Meanwhile, a third paper reports on yet another protein that binds to NgR — oligodendrocyte-myelin glycoprotein (OMgp). Wang et al. showed that this previously identified protein also inhibits neurite outgrowth in a NgR-dependent way, and that receptor expression confers OMgp responsiveness on insensitive neurons. Moreover, Wang et al. found that OMgp and Nogo bind to overlapping sites on NgR.

So, three myelin proteins that inhibit axon outgrowth share the same receptor. This fact compels us to take a closer look at the intracellular processes downstream of NgR. Intriguingly, the inhibitory effect of myelin is blocked if the small GTPase Rho is inactivated or if cyclic AMP is elevated, pointing to these signalling molecules as possible transducers of the NgR signal. But as NgR is a glycosylphosphatidylinositol-anchored protein, we still need to discover further molecules that interact with ligand and receptor, linking them to these signalling pathways.