A p75^NTR and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein

Myelin-associated glycoprotein (MAG), an inhibitor of axon regeneration, binds with high affinity to the Nogo-66 receptor (NgR). Here we report that the p75 neurotrophin receptor (p75^NTR) is a coreceptor of NgR for MAG signaling. In cultured human embryonic kidney (HEK) cells expressing NgR, p75^NTR was required for MAG-induced intracellular Ca²⁺ elevation. Co-immunoprecipitation showed an association of NgR with p75^NTR that can be disrupted by an antibody against p75^NTR (NGFR5), and extensive coexpression was observed in the developing rat nervous system. Furthermore, NGFR5 abolished MAG-induced repulsive turning of Xenopus axonal growth cones and Ca²⁺ elevation, both in neurons and in NgR/p75^NTR-expressing HEK cells. Thus we conclude that p75^NTR is a co-receptor of NgR for MAG signaling and a potential therapeutic target for promoting nerve regeneration.