Department of Neurology and Neuroscience, New Jersey Medical School Cancer Center, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103, and Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, Colorado 80045.
J Neurosci. 2014 Mar 26;34(13):4453-65. doi: 10.1523/JNEUROSCI.4311-13.2014.
Prior studies support a role for mammalian target of rapamycin (mTOR) signaling in oligodendrocyte differentiation and myelination. Here we use Cre-recombinase driven by the CNP promoter to generate a mouse line with oligodendrocyte-specific knockdown of mTOR (mTOR cKO) in the CNS. We provide evidence that mTOR is necessary for proper oligodendrocyte differentiation and myelination in the spinal cord. Specifically, the number of mature oligodendrocytes was reduced, and the initiation and extent of myelination were impaired during spinal cord development. Consistent with these data, myelin protein expression, including myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein, and myelin-associated glycoprotein, was delayed in the spinal cord. Hypomyelination of the spinal cord persisted into adulthood, as did the reduction in numbers of mature oligodendrocytes. In the cortex, the structure of myelin appeared normal during development and in the adult; however, myelin protein expression was delayed during development and was abnormal in the adult. Myelin basic protein was significantly reduced in all regions at postnatal day 25. These data demonstrate that mTOR promotes oligodendrocyte differentiation and CNS myelination in vivo and show that the requirement for mTOR varies by region with the spinal cord most dependent on mTOR.
先前的研究支持雷帕霉素靶蛋白（mTOR）信号在少突胶质细胞分化和髓鞘形成中的作用。在这里，我们使用 CNP 启动子驱动的 Cre 重组酶在 CNS 中产生少突胶质细胞特异性 mTOR 敲低（mTOR cKO）的小鼠品系。我们提供的证据表明，mTOR 是脊髓中少突胶质细胞分化和髓鞘形成所必需的。具体来说，成熟少突胶质细胞的数量减少，并且在脊髓发育过程中髓鞘形成的起始和程度受损。与这些数据一致，髓鞘蛋白表达，包括髓鞘碱性蛋白、髓鞘蛋白脂质蛋白、少突胶质细胞糖蛋白和髓鞘相关糖蛋白，在脊髓中延迟。脊髓的低髓鞘化持续到成年期，成熟少突胶质细胞的数量减少也是如此。在皮质中，髓鞘的结构在发育过程中和成年期都是正常的；然而，髓鞘蛋白的表达在发育过程中延迟，在成年期异常。髓鞘碱性蛋白在出生后第 25 天所有区域均显著减少。这些数据表明 mTOR 在体内促进少突胶质细胞分化和中枢神经系统髓鞘形成，并表明 mTOR 的需求因区域而异，脊髓对 mTOR 的依赖性最大。
