Conditional Ablation of Raptor or Rictor Has Differential Impact on Oligodendrocyte Differentiation and CNS Myelination
Conditional Ablation of Raptor or Rictor Has Differential Impact on Oligodendrocyte Differentiation and CNS Myelination
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DOI：
10.1523/jneurosci.4314-13.2014
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发表时间：
2014-03-26
影响因子：
5.3
通讯作者：
Macklin, Wendy B.
中科院分区：
文献类型：
--
作者：
Bercury, Kathryn K.;Dai, JinXiang;Macklin, Wendy B.
在中枢神经系统发育过程中，少突胶质细胞--中枢神经系统的髓鞘胶质细胞--经历了多个短暂阶段，最终形成完全成熟的细胞。少突胶质细胞的分化和髓鞘形成是一个严格调控的过程，需要细胞外信号汇聚以引发特定的翻译和转录变化。我们的实验室先前已经证明，蛋白激酶Akt和哺乳动物雷帕霉素靶标(MTOR)是体内中枢神经系统髓鞘形成的重要调节因子。MTOR通过两个不同的复合体，mTOR复合体1(MTORC1)和mTORC2，分别与Raptor或Rictor结合发挥作用。为了确定mTOR对CNS髓鞘形成的影响是否是由于在CNS髓鞘形成过程中mTORC1或mTORC2的独特功能，我们在体内有条件地消融了少突胶质细胞谱系中的Raptor或Rictor。我们发现，当mTORC2功能正常时，Raptor(MTORC1)是发育中的CNS小鼠髓鞘形成的正调控因子，而当mTORC2功能正常时，Rictor(MTORC2)对少突胶质细胞的分化有适度的积极影响，而对髓鞘形成的影响很小。此外，我们还发现少突胶质细胞中Raptor的缺失会导致中枢神经系统特定区域的不同程度的髓鞘异常，对脊髓髓鞘形成的影响最大。
During CNS development, oligodendrocytes, the myelinating glia of the CNS, progress through multiple transitory stages before terminating into fully mature cells. Oligodendrocyte differentiation and myelination is a tightly regulated process requiring extracellular signals to converge to elicit specific translational and transcriptional changes. Our lab has previously shown that the protein kinases, Akt and mammalian Target of Rapamycin (mTOR), are important regulators of CNS myelination in vivo. mTOR functions through two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2, by binding to either Raptor or Rictor, respectively. To establish whether the impact of mTOR on CNS myelination results from unique functions of mTORC1 or mTORC2 during CNS myelination, we conditionally ablated either Raptor or Rictor in the oligodendrocyte lineage, in vivo. We show that Raptor (mTORC1) is a positive regulator of developmental CNS mouse myelination when mTORC2 is functional, whereas Rictor (mTORC2) ablation has a modest positive effect on oligodendrocyte differentiation, and very little effect on myelination, when mTORC1 is functional. Also, we show that loss of Raptor in oligodendrocytes results in differential dysmyelination in specific areas of the CNS, with the greatest impact on spinal cord myelination.