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 af...

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Bibliographic Details
Published in:Molecular and cellular neuroscience 2011-01, Vol.46 (1), p.235-244
Main Authors: Perdigoto, Ana Luisa, Chaudhry, Nagarathnamma, Barnes, Gregory N., Filbin, Marie T., Carter, Bruce D.
Format: Article
Language:English
Subjects:
AKT
Animals
Cells, Cultured
Cerebral Cortex - cytology
CHO Cells
Coculture Techniques
Cortical
Cricetinae
Cricetulus
HEK293 Cells
Humans
MAG
Mice
Mice, Inbred C57BL
Mice, Knockout
Myelin-Associated Glycoprotein - genetics
Myelin-Associated Glycoprotein - metabolism
Neurites - physiology
Neurites - ultrastructure
Neuron
Neurons - cytology
Neurons - physiology
Outgrowth
Proto-Oncogene Proteins c-akt - genetics
Proto-Oncogene Proteins c-akt - metabolism
PTEN
PTEN Phosphohydrolase - genetics
PTEN Phosphohydrolase - metabolism
Receptor, Nerve Growth Factor - metabolism
rho GTP-Binding Proteins - metabolism
rho-Associated Kinases
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Summary: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.
ISSN:1044-7431
1095-9327
DOI:10.1016/j.mcn.2010.09.006