Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth.
Myelin inhibitors of axonal regeneration, like Nogo and MAG, block regrowth after injury to the adult CNS. While a GPI-linked receptor for Nogo (NgR) has been identified, MAG's receptor is unknown. We show that MAG inhibits regeneration by interaction with NgR. Binding of and inhibition by MAG are lost if neuronal GPI-linked proteins are cleaved. Binding of MAG to NgR-expressing cells is GPI dependent and sialic acid independent. Conversely, NgR binds to MAG-expressing cells. MAG, but not a truncated MAG that binds neurons but does not inhibit regeneration, precipitates NgR from NgR-expressing cells, DRG, and cerebellar neurons. Importantly, NgR antibody, soluble NgR, or dominant-negative NgR each prevent inhibition of neurite outgrowth by MAG. Also, MAG and Nogo66 compete for binding to NgR. These results suggest redundancy in myelin inhibitors and indicate therapies for CNS injuries.
Domeniconi
Marco
M
The Department of Biological Sciences, Hunter College, City University of New York, 695 Park Avenue, New York, NY 10021, USA.
Cao
Zixuan
Z
Spencer
Timothy
T
Sivasankaran
Rajeev
R
Wang
Kevin
K
Nikulina
Elena
E
Kimura
Noriko
N
Cai
Hong
H
Deng
Kangwen
K
Gao
Ying
Y
He
Zhigang
Z
Filbin
Marie
M
D000818:Animals; D000831:Animals, Newborn; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002490:Central Nervous System / Q000166:cytology / Q000254:growth & development* / Q000293:injuries*; D006224:Cricetinae; D058851:GPI-Linked Proteins; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D020439:Growth Cones / Q000378:metabolism / Q000648:ultrastructure; D006133:Growth Substances / Q000378:metabolism; D007150:Immunohistochemistry; D009185:Myelin Proteins / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism; D018992:Myelin-Associated Glycoprotein / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000648:ultrastructure; D009416:Nerve Regeneration / Q000502:physiology*; D016501:Neurites / Q000378:metabolism* / Q000648:ultrastructure; D000070816:Nogo Receptor 1; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism*
D058851:GPI-Linked Proteins; D017261:Glycosylphosphatidylinositols; D006133:Growth Substances; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; C457761:NEPI-40 protein, rat; D000070816:Nogo Receptor 1; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; C486581:Rtn4r protein, rat; D019158:N-Acetylneuraminic Acid