1. Division of Neuroscience, Children's Hospital, Harvard Medical School, 320 Longwood Avenue, Boston, Massachusetts 02115, USA
2. Program in Neuroscience, Harvard Medical School, 320 Longwood Avenue, Boston, Massachusetts 02115, USA
3. Department of Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
4. These authors contributed equally to this work

Correspondence to: Zhigang He^1,2 Correspondence and requests for materials should be addressed to Z.H. (e-mail: Email: zhigang.he@tch.harvard.edu).

Abstract

In inhibiting neurite outgrowth, several myelin components, including the extracellular domain of Nogo-A (Nogo-66)¹, oligodendrocyte myelin glycoprotein (OMgp)² and myelin-associated glycoprotein (MAG)^{3, 4}, exert their effects through the same Nogo receptor (NgR). The glycosyl phosphatidylinositol (GPI)-anchored nature of NgR indicates the requirement for additional transmembrane protein(s) to transduce the inhibitory signals into the interior of responding neurons. Here, we demonstrate that p75, a transmembrane protein known to be a receptor for the neurotrophin family of growth factors^{5, 6}, specifically interacts with NgR. p75 is required for NgR-mediated signalling, as neurons from p75 knockout mice are no longer responsive to myelin and to each of the known NgR ligands. Blocking the p75–NgR interaction also reduces the activities of these inhibitors. Moreover, a truncated p75 protein lacking the intracellular domain, when overexpressed in primary neurons, attenuates the same set of inhibitory activities, suggesting that p75 is a signal transducer of the NgR–p75 receptor complex. Thus, interfering with p75 and its downstream signalling pathways may allow lesioned axons to overcome most of the inhibitory activities associated with central nervous system myelin.