Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology, ETH Zürich, CH-8093 Zürich, Switzerland.
Core Facility for Mass Spectrometry/Lipidomics, Center for Medical Research, Medical University of Graz, 8010 Graz, Austria, Omics Center Graz, 8010 Graz, Austria, and.
J Neurosci. 2014 Jun 18;34(25):8432-48. doi: 10.1523/JNEUROSCI.1105-14.2014.
The mammalian target of rapamycin (mTOR) pathway integrates multiple signals and regulates crucial cell functions via the molecular complexes mTORC1 and mTORC2. These complexes are functionally dependent on their raptor (mTORC1) or rictor (mTORC2) subunits. mTOR has been associated with oligodendrocyte differentiation and myelination downstream of the PI3K/Akt pathway, but the functional contributions of individual complexes are largely unknown. We show, by oligodendrocyte-specific genetic deletion of Rptor and/or Rictor in the mouse, that CNS myelination is mainly dependent on mTORC1 function, with minor mTORC2 contributions. Myelin-associated lipogenesis and protein gene regulation are strongly reliant on mTORC1. We found that also oligodendrocyte-specific overactivation of mTORC1, via ablation of tuberous sclerosis complex 1 (TSC1), causes hypomyelination characterized by downregulation of Akt signaling and lipogenic pathways. Our data demonstrate that a delicately balanced regulation of mTORC1 activation and action in oligodendrocytes is essential for CNS myelination, which has practical overtones for understanding CNS myelin disorders.
哺乳动物雷帕霉素靶蛋白（mTOR）途径通过分子复合物 mTORC1 和 mTORC2 整合多种信号并调节关键的细胞功能。这些复合物的功能依赖于它们的 Raptor（mTORC1）或 Rictor（mTORC2）亚基。mTOR 与 PI3K/Akt 途径下游的少突胶质细胞分化和髓鞘形成有关，但单个复合物的功能贡献在很大程度上尚不清楚。我们通过在小鼠中特异性敲除少突胶质细胞的 Rptor 和/或 Rictor，表明中枢神经系统髓鞘形成主要依赖于 mTORC1 功能，而 mTORC2 的贡献较小。髓鞘相关脂生成和蛋白质基因调控强烈依赖于 mTORC1。我们发现，通过消融结节性硬化复合物 1（TSC1）特异性地过度激活 mTORC1，也会导致 Akt 信号和脂生成途径下调的少突胶质细胞 hypomyelination。我们的数据表明，在少突胶质细胞中精细平衡地调节 mTORC1 的激活和作用对于中枢神经系统髓鞘形成至关重要，这对于理解中枢神经系统髓鞘疾病具有实际意义。
