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p75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp

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 factors5,6, 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.

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Figure 1: p75 and NgR form receptor complexes.
Figure 2: p75 is required for the inhibitory activities of myelin inhibitors.
Figure 3: The p75–NgR interaction is required for the inhibitory responses to myelin inhibitors.
Figure 4: The intracellular domain of p75 is required for p75–NgR signalling.

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Acknowledgements

We thank S. Birren and M. Chao for providing some of the p75 mutant mice and constructs; K. Gerhold for technical assistance; K.-F. Lee for discussion; and M. Greenberg, V. Koprivica and K.-F. Lee for critical reading of the manuscript. This study was supported by the Alfred Sloan Foundation, the Burrough Wellcome Fund, the EJLB Foundation, the International Spinal Research Trust, the John Merck Fund, the Klingenstein Fund, the Whitehall Foundation, the National Institute of Drug Abuse, and the National Institute of Neurological Disorders and Stroke (to Z.H.). K.C.W. is a recipient of a Howard Hughes Predoctoral Fellowship. R.S. is supported by a postdoctoral fellowship from the Lefler Foundation.

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Correspondence to Zhigang He.

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Wang, K., Kim, J., Sivasankaran, R. et al. p75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420, 74–78 (2002). https://doi.org/10.1038/nature01176

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