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A novel role for PTEN in the inhibition of neurite outgrowth by myelin-associated glycoprotein in cortical neurons

机译:PTEN在皮层神经元的髓鞘相关糖蛋白抑制神经突增生中的新作用

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摘要

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.
机译:中枢神经系统中的轴突再生部分地被髓磷脂表达的抑制性蛋白质阻止,包括髓磷脂相关糖蛋白(MAG)。尽管皮质脊髓束损伤可导致永久性残疾,但关于MAG影响皮质神经元的机制知之甚少。在这里,我们证明镀在表达MAG的CHO细胞上的皮质神经元表现出惊人的过程生长减少。有趣的是,以前与MAG信号有关的任何受体,包括p75神经营养因子受体或神经节苷脂,均未对MAG介导的抑制作用有明显贡献。但是,阻断小GTPase Rho或其下游效应激酶ROCK可以部分逆转MAG对神经元的作用。此外,我们确定了脂质磷酸酶PTEN作为MAG对神经突生长抑制作用的介体。 PTEN的基因敲除或基因缺失或激活的AKT在皮质神经元中的过度表达可导致MAG-CHO细胞上神经突增生的明显(尽管部分)得以挽救。此外,MAG降低了磷酸化Akt的水平,表明它激活了神经元中的PTEN。两者合计,这些结果表明,MAG激活了皮层神经元中涉及PTEN / PI3K / AKT轴的新型途径。

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