PTEN negatively regulates the cell lineage progression from NG2(+) glial progenitor to oligodendrocyte via mTOR-independent signaling.
PTEN negatively regulates the cell lineage progression from NG2(+) glial progenitor to oligodendrocyte via mTOR-independent signaling.
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DOI：
10.7554/elife.32021
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发表时间：
2018-02-20
期刊：
影响因子：
7.7
通讯作者：
Kang SH
中科院分区：
文献类型：
--
作者：
González-Fernández E;Jeong HK;Fukaya M;Kim H;Khawaja RR;Srivastava IN;Waisman A;Son YJ;Kang SH
少突胶质细胞 (OL) 是形成髓磷脂的中枢神经系统胶质细胞，非常容易受到细胞应激的影响，严重的髓磷脂缺失是许多中枢神经系统疾病的基础。加速 OL 再生可以防止进一步的轴突损伤并促进中枢神经系统功能修复。尽管成体 OL 祖细胞 (OPC) 是 OL 再生的主要参与者，但促进 OL 再生的可靶向 OPC 特异性细胞内信号传导机制仍然难以捉摸。在这里，我们报告说，与 OL 特异性操作相比，小鼠中 OPC 靶向的 PTEN 失活显着促进了成熟中枢神经系统中 OL 的分化和再生。出乎意料的是，额外删除 mTOR 并没有逆转 PTEN 缺陷的 OPC 增强的 OL 发育。相反，GSK3β（另一种受 PTEN-Akt 负向调节的下游信号分子）的消除增强了 OL 的发育。我们的结果表明，PTEN 以不依赖于 mTOR 的方式持续抑制 OL 发育，并且至少部分是通过控制 GSK3β 活性。 OPC 靶向的 PTEN-GSK3β 失活可能有利于促进 OL 再生和髓磷脂修复。
Oligodendrocytes (OLs), the myelin-forming CNS glia, are highly vulnerable to cellular stresses, and a severe myelin loss underlies numerous CNS disorders. Expedited OL regeneration may prevent further axonal damage and facilitate functional CNS repair. Although adult OL progenitors (OPCs) are the primary players for OL regeneration, targetable OPC-specific intracellular signaling mechanisms for facilitated OL regeneration remain elusive. Here, we report that OPC-targeted PTEN inactivation in the mouse, in contrast to OL-specific manipulations, markedly promotes OL differentiation and regeneration in the mature CNS. Unexpectedly, an additional deletion of mTOR did not reverse the enhanced OL development from PTEN-deficient OPCs. Instead, ablation of GSK3β, another downstream signaling molecule that is negatively regulated by PTEN-Akt, enhanced OL development. Our results suggest that PTEN persistently suppresses OL development in an mTOR-independent manner, and at least in part, via controlling GSK3β activity. OPC-targeted PTEN-GSK3β inactivation may benefit facilitated OL regeneration and myelin repair.