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 co-receptor 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.
Wong
Scott T
ST
Division of Neurobiology, Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
Henley
John R
JR
Kanning
Kevin C
KC
Huang
Kuo-hua
KH
Bothwell
Mark
M
Poo
Mu-ming
MM
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002462:Cell Membrane / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D004625:Embryo, Nonmammalian; D005333:Fetus; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism* / Q000494:pharmacology; D009416:Nerve Regeneration / Q000187:drug effects / Q000235:genetics*; D000070798:Nogo Proteins; D051381:Rats; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014981:Xenopus
D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D000070798:Nogo Proteins; C000603199:RTN4 protein, human; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; C000603197:Rtn4 protein, rat