Oligodendrocyte Precursor Cell-Intrinsic Effect of Rheb1 Controls Differentiation and Mediates mTORC1-Dependent Myelination in Brain
Oligodendrocyte Precursor Cell-Intrinsic Effect of Rheb1 Controls Differentiation and Mediates mTORC1-Dependent Myelination in Brain
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Rheb1 的少突胶质细胞前体细胞内在作用控制分化并介导大脑中 mTORC1 依赖性髓鞘形成
DOI：
10.1523/jneurosci.2267-14.2014
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发表时间：
2014-11
影响因子：
5.3
通讯作者：
Xiao Bo
中科院分区：
文献类型：
--
作者：
Zou Yi;Jiang Wanxiang;Wang Jianqing;Li Zhongping;Zhang Junyan;Bu Jicheng;Zou Jia;Zhou Liang;Yu Shouyang;Cui Yiyuan;Yang Weiwei;Luo Liping;Lu Qing R.;Liu Yanhui;Chen Mina;Worley Paul F.;Xiao Bo
Rheb 1是一个立即早期基因，其功能是选择性激活哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）。我们以前已经证明，Rheb 1是必不可少的髓鞘形成在中枢神经系统中使用巢蛋白-Cre驱动线删除Rheb 1在所有神经细胞谱系，和最近的研究使用少突胶质细胞特异性CNP-Cre已经表明，mTORC 1的优先作用是在脊髓髓鞘形成。在这里，我们研究了Rheb 1/mTORC 1在小鼠少突胶质细胞谱系中的作用，使用单独的Cre驱动程序，用于少突胶质细胞祖细胞（OPC），包括Olig 1-Cre和Olig 2-Cre，以及分化和成熟的少突胶质细胞，包括CNP-Cre和Tmem 10-Cre。OPCs中Rheb 1的缺失损害其向成熟少突胶质细胞的分化。这是伴随着减少OPC细胞周期退出表明在OPC分化的Rheb 1的要求。Rheb 1对OPC分化的影响是由mTor介导的，因为mTor的Olig 1-Cre缺失表型模仿Olig 1-Cre Rheb 1缺失。相反，成熟少突胶质细胞中Rheb 1的缺失不会破坏发育髓鞘形成或髓鞘维持。如泛星形胶质细胞标志物Aldh 1 L1所示，OPCs或神经祖细胞中Rheb 1的缺失不影响灰色和白色物质中星形胶质细胞的形成。我们的结论是，OPC内在的mTORC 1活性介导的Rheb 1是至关重要的分化的OPC成熟的少突胶质细胞，但成熟的少突胶质细胞不需要Rheb 1使髓鞘或维持它在成年人的大脑。这些研究揭示了可能与髓鞘疾病中髓鞘形成发育和髓鞘再生受损相关的机制。
Rheb1 is an immediate early gene that functions to activate mammalian target of rapamycin (mTor) selectively in complex 1 (mTORC1). We have demonstrated previously that Rheb1 is essential for myelination in the CNS using a Nestin-Cre driver line that deletes Rheb1 in all neural cell lineages, and recent studies using oligodendrocyte-specific CNP-Cre have suggested a preferential role for mTORC1 is myelination in the spinal cord. Here, we examine the role of Rheb1/mTORC1 in mouse oligodendrocyte lineage using separate Cre drivers for oligodendrocyte progenitor cells (OPCs) including Olig1-Cre and Olig2-Cre as well as differentiated and mature oligodendrocytes including CNP-Cre and Tmem10-Cre. Deletion of Rheb1 in OPCs impairs their differentiation to mature oligodendrocytes. This is accompanied by reduced OPC cell-cycle exit suggesting a requirement for Rheb1 in OPC differentiation. The effect of Rheb1 on OPC differentiation is mediated by mTor since Olig1-Cre deletion of mTor phenocopies Olig1-Cre Rheb1 deletion. Deletion of Rheb1 in mature oligodendrocytes, in contrast, does not disrupt developmental myelination or myelin maintenance. Loss of Rheb1 in OPCs or neural progenitors does not affect astrocyte formation in gray and white matter, as indicated by the pan-astrocyte marker Aldh1L1. We conclude that OPC-intrinsic mTORC1 activity mediated by Rheb1 is critical for differentiation of OPCs to mature oligodendrocytes, but that mature oligodendrocytes do not require Rheb1 to make myelin or maintain it in the adult brain. These studies reveal mechanisms that may be relevant for both developmental myelination and impaired remyelination in myelin disease.
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影响因子：
64.5
作者：
K. Sanada;L. Tsai
通讯作者：
K. Sanada;L. Tsai
影响因子：
50.3
作者：
Schueller, Ulrich;Heine, Vivi M.;Mao, Junhao;Kho, Alvin T.;Dillon, Allison K.;Han, Young-Goo;Huillard, Emmanuelle;Sun, Tao;Ligon, Azra H.;Qian, Ying;Ma, Qiufu;Alvarez-Buylla, Arturo;McMahon, Andrew P.;Rowitch, David H.;Ligon, Keith L.
通讯作者：
Ligon, Keith L.
影响因子：
30.8
作者：
Lappe-Siefke, C;Goebbels, S;Nave, KA
通讯作者：
Nave, KA
影响因子：
64.8
作者：
Cunningham, John T.;Rodgers, Joseph T.;Puigserver, Pere
通讯作者：
Puigserver, Pere
影响因子：
5.3
作者：
Magri, Laura;Swiss, Victoria A.;Casaccia, Patrizia
通讯作者：
Casaccia, Patrizia