A novel role for PTEN in the inhibition of neurite outgrowth by myelin-associated glycoprotein in cortical neurons.
Axonal regeneration in the central nervous system is prevented, in part, by inhibitory proteins expressed by myelin, including myelin-associated glycoprotein (MAG). Although injury to the corticospinal tract can result in permanent disability, little is known regarding the mechanisms by which MAG affects cortical neurons. Here, we demonstrate that cortical neurons plated on MAG expressing CHO cells, exhibit a striking reduction in process outgrowth. Interestingly, none of the receptors previously implicated in MAG signaling, including the p75 neurotrophin receptor or gangliosides, contributed significantly to MAG-mediated inhibition. However, blocking the small GTPase Rho or its downstream effector kinase, ROCK, partially reversed the effects of MAG on the neurons. In addition, we identified the lipid phosphatase PTEN as a mediator of MAG's inhibitory effects on neurite outgrowth. Knockdown or gene deletion of PTEN or overexpression of activated AKT in cortical neurons resulted in significant, although partial, rescue of neurite outgrowth on MAG-CHO cells. Moreover, MAG decreased the levels of phospho-Akt, suggesting that it activates PTEN in the neurons. Taken together, these results suggest a novel pathway activated by MAG in cortical neurons involving the PTEN/PI3K/AKT axis.
Perdigoto
Ana Luisa
AL
Department of Biochemistry and the Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Chaudhry
Nagarathnamma
N
Barnes
Gregory N
GN
Filbin
Marie T
MT
Carter
Bruce D
BD
D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D018920:Coculture Techniques; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018992:Myelin-Associated Glycoprotein / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000502:physiology* / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases
D018992:Myelin-Associated Glycoprotein; D020800:Receptor, Nerve Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; D051059:PTEN Phosphohydrolase; D020741:rho GTP-Binding Proteins