Molecular dissection of the myelin-associated glycoprotein receptor complex reveals cell type-specific mechanisms for neurite outgrowth inhibition.
Neuronal Nogo66 receptor-1 (NgR1) binds the myelin inhibitors NogoA, OMgp, and myelin-associated glycoprotein (MAG) and has been proposed to function as the ligand-binding component of a receptor complex that also includes Lingo-1, p75(NTR), or TROY. In this study, we use Vibrio cholerae neuraminidase (VCN) and mouse genetics to probe the molecular composition of the MAG receptor complex in postnatal retinal ganglion cells (RGCs). We find that VCN treatment is not sufficient to release MAG inhibition of RGCs; however, it does attenuate MAG inhibition of cerebellar granule neurons. Furthermore, the loss of p75(NTR) is not sufficient to release MAG inhibition of RGCs, but p75(NTR-/-) dorsal root ganglion neurons show enhanced growth on MAG compared to wild-type controls. Interestingly, TROY is not a functional substitute for p75(NTR) in RGCs. Finally, NgR1(-/-) RGCs are strongly inhibited by MAG. In the presence of VCN, however, NgR1(-/-) RGCs exhibit enhanced neurite growth. Collectively, our experiments reveal distinct and cell type-specific mechanisms for MAG-elicited growth inhibition.
Venkatesh
Karthik
K
Interdepartmental Graduate Program in Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Chivatakarn
Onanong
O
Sheu
Shey-Shing
SS
Giger
Roman J
RJ
D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D058851:GPI-Linked Proteins; D005727:Ganglia, Spinal / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009185:Myelin Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018992:Myelin-Associated Glycoprotein; D009439:Neuraminidase / Q000737:chemistry; D016501:Neurites / Q000737:chemistry / Q000378:metabolism*; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D051381:Rats; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D014734:Vibrio cholerae / Q000201:enzymology
D001426:Bacterial Proteins; D058851:GPI-Linked Proteins; C104739:Mag protein, mouse; D046912:Multiprotein Complexes; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D011956:Receptors, Cell Surface; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C000603201:Rtn4 protein, mouse; C000603197:Rtn4 protein, rat; C419790:Rtn4r protein, mouse; C517634:Ngfr protein, mouse; C409471:Tnfrsf19 protein, mouse; D009439:Neuraminidase