mTORC1 Controls PNS Myelination along the mTORC1-RXRγ-SREBP-Lipid Biosynthesis Axis in Schwann Cells

• Published in: Cell reports (Cambridge) Vol. 9; no. 2; pp. 646 - 660
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.10.2014; Elsevier
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Cells, Cultured; Lipids - biosynthesis; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Myelin Sheath - metabolism; Peripheral Nervous System - growth & development; Peripheral Nervous System - metabolism; Peripheral Nervous System - physiology; Regulatory-Associated Protein of mTOR; Retinoid X Receptor gamma - metabolism; Schwann Cells - metabolism; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.09.001

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. [Display omitted] •Loss of mTORC1, but not mTORC2, in Schwann cells leads to PNS hypomyelination•Altered lipid composition and decreased nerve conduction accompany the hypomyelination•mTORC1 deficiency causes defective SREBP signaling•In Schwann cells, RXRγ regulates SREBP1c expression downstream of mTORC1 Here, Norrmén et al. identify a central role for the mTORC1 complex in peripheral nerve myelination and provide evidence that SREBPs are key effectors of mTORC1 in regulating Schwann cell lipid biogenesis. They establish the nuclear receptor RXRγ as a downstream target of mTORC1 signaling and show that RXRγ transcriptionally regulates SREBP1c, thus controlling fatty acid metabolism.