Nogo receptor 3, a paralog of Nogo-66 receptor 1 (NgR1), may function as a NgR1 co-receptor for Nogo-66

Nogo-A is a major myelin associated inhibitor that blocks regeneration of injured axons in the central nervous system (CNS). Nogo-66 (a 66-residue domain of Nogo-A) expressed on the surface of oligodendrocytes has been shown to directly interact with Nogo-66 receptor 1 (NgR1). A number of additional components of NgR1 receptor complex essential for its signaling have been uncovered. However, detailed composition of the complex and its signaling mechanisms remain to be fully elucidated. In this study, we show that Nogo receptor 3 (NgR3), a paralog of NgR1, is a binding protein for NgR1. The interaction is highly specific because other members of the reticulin family, to which Nogo-A belongs, do not bind to NgR3. Neither does NgR3 show any binding activity with Nogo receptor 2 (NgR2), another NgR1 paralog. Majority of NgR3 domains are required for its binding to NgR1. Moreover, a truncated NgR3 with the membrane anchoring domain deleted can function as a decoy receptor to reverse neurite outgrowth inhibition caused by Nogo-66 in culture. These in vitro results, together with previously reported overlapping expression profile between NgR1 and NgR3, suggest that NgR3 may be associated with NgR1 in vivo and that their binding interface may be targeted for treating neuronal injuries.