Norrmén Camilla, Figlia Gianluca, Lebrun-Julien Frédéric, Pereira Jorge A, Trötzmüller Martin, Köfeler Harald C, Rantanen Ville, Wessig Carsten, van Deijk Anne-Lieke F, Smit August B, Verheijen Mark H G, Rüegg Markus A, Hall Michael N, Suter Ueli
Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology Zurich, ETH Zürich, CH-8093 Zurich, Switzerland.
Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology Zurich, ETH Zürich, CH-8093 Zurich, Switzerland.
Cell Rep. 2014 Oct 23;9(2):646-60. doi: 10.1016/j.celrep.2014.09.001. Epub 2014 Oct 9.
Myelin formation during peripheral nervous system (PNS) development, and reformation after injury and in disease, requires multiple intrinsic and extrinsic signals. Akt/mTOR signaling has emerged as a major player involved, but the molecular mechanisms and downstream effectors are virtually unknown. Here, we have used Schwann-cell-specific conditional gene ablation of raptor and rictor, which encode essential components of the mTOR complexes 1 (mTORC1) and 2 (mTORC2), respectively, to demonstrate that mTORC1 controls PNS myelination during development. In this process, mTORC1 regulates lipid biosynthesis via sterol regulatory element-binding proteins (SREBPs). This course of action is mediated by the nuclear receptor RXRγ, which transcriptionally regulates SREBP1c downstream of mTORC1. Absence of mTORC1 causes delayed myelination initiation as well as hypomyelination, together with abnormal lipid composition and decreased nerve conduction velocity. Thus, we have identified the mTORC1-RXRγ-SREBP axis controlling lipid biosynthesis as a major contributor to proper peripheral nerve function.
外周神经系统（PNS）发育过程中的髓鞘形成，以及损伤后和疾病状态下的髓鞘重塑，需要多种内在和外在信号。Akt/mTOR信号通路已成为其中的一个主要参与者，但其分子机制和下游效应器几乎仍不清楚。在这里，我们利用分别编码mTOR复合物1（mTORC1）和2（mTORC2）关键成分的猛禽（raptor）和rictor在雪旺细胞中的特异性条件性基因敲除，来证明mTORC1在发育过程中控制PNS髓鞘形成。在此过程中，mTORC1通过固醇调节元件结合蛋白（SREBPs）调节脂质生物合成。这一作用过程由核受体RXRγ介导，RXRγ在转录水平上调节mTORC1下游的SREBP1c。mTORC1的缺失导致髓鞘形成起始延迟以及髓鞘形成不足，同时伴有脂质组成异常和神经传导速度降低。因此，我们确定了控制脂质生物合成的mTORC1-RXRγ-SREBP轴是外周神经正常功能的主要贡献因素。
