title: mTORC1 controls PNS myelination along the mTORC1-RXRγ-SREBP-lipid biosynthesis axis in Schwann cells.
abstract: 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.
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology Zurich, ETH Zürich, CH-8093 Zurich, Switzerland. Electronic address: camilla.norrmen@biol.ethz.ch.
authors.forename: Camilla
authors.initials: C
authors.lastname: Norrmén
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology Zurich, ETH Zürich, CH-8093 Zurich, Switzerland.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Figlia
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology Zurich, ETH Zürich, CH-8093 Zurich, Switzerland.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lebrun-Julien
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology Zurich, ETH Zürich, CH-8093 Zurich, Switzerland.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Pereira
authors.affiliation: Core Facility for Mass Spectrometry, Center for Medical Research, Medical University of Graz, 8010 Graz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Trötzmüller
authors.affiliation: Core Facility for Mass Spectrometry, Center for Medical Research, Medical University of Graz, 8010 Graz, Austria.
authors.forename: Harald C
authors.initials: HC
authors.lastname: Köfeler
authors.affiliation: Research Programs Unit, Genome-Scale Biology, and Institute of Biomedicine, Biochemistry and Developmental Biology, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Rantanen
authors.affiliation: Department of Neurology, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Wessig
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081HV Amsterdam, the Netherlands.
authors.forename: Anne-Lieke F
authors.initials: AL
authors.lastname: van Deijk
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081HV Amsterdam, the Netherlands.
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, 1081HV Amsterdam, the Netherlands.
authors.forename: Mark H G
authors.initials: MH
authors.lastname: Verheijen
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology Zurich, ETH Zürich, CH-8093 Zurich, Switzerland. Electronic address: ueli.suter@biol.ethz.ch.
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D008055:Lipids / Q000096:biosynthesis; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism*; D017933:Peripheral Nervous System / Q000254:growth & development / Q000378:metabolism* / Q000502:physiology; D000076223:Regulatory-Associated Protein of mTOR; D047491:Retinoid X Receptor gamma / Q000378:metabolism*; D012583:Schwann Cells / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008055:Lipids; D046912:Multiprotein Complexes; D000076223:Regulatory-Associated Protein of mTOR; D047491:Retinoid X Receptor gamma; C540162:Rptor protein, mouse; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases