A novel role for PTEN in the inhibition of neurite outgrowth by myelin-associated glycoprotein in cortical neurons.
A novel role for PTEN in the inhibition of neurite outgrowth by myelin-associated glycoprotein in cortical neurons.
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DOI：
10.1016/j.mcn.2010.09.006
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发表时间：
2011-01
影响因子：
3.5
通讯作者：
Carter, Bruce D.
中科院分区：
文献类型：
--
作者：
Perdigoto, Ana Luisa;Chaudhry, Nagarathnamma;Barnes, Gregory N.;Filbin, Marie T.;Carter, Bruce D.
中枢神经系统中的轴突再生在一定程度上是由髓鞘表达的抑制蛋白阻止的，包括髓鞘相关糖蛋白(MAG)。虽然皮质脊髓束损伤可导致永久性残疾，但对MAG影响皮质神经元的机制知之甚少。在这里，我们证明了在MAG上电镀表达CHO细胞的皮质神经元，表现出突起生长的显著减少。有趣的是，之前涉及MAG信号的受体，包括p75神经营养素受体或神经节苷脂，都没有对MAG介导的抑制起到显著作用。然而，阻断小的GTP酶Rho或其下游的效应激酶ROCK，部分逆转了MAG对神经元的影响。此外，我们还发现脂质磷酸酶PTEN是MAG抑制神经突起生长的中介分子。在皮质神经元中，PTEN基因的敲除或基因缺失或激活的AKT的过度表达导致MAG-CHO细胞突起生长的显著挽救，尽管是部分的。此外，MAG降低了磷酸化Akt的水平，提示它激活了神经元中的PTEN。综上所述，这些结果提示了MAG激活皮层神经元的一条新的途径，涉及PTEN/PI3K/AKT轴。
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 over expression 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.
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