title: Balanced mTORC1 activity in oligodendrocytes is required for accurate CNS myelination.
abstract: 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.
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology, ETH Zürich, CH-8093 Zürich, 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, ETH Zürich, CH-8093 Zürich, Switzerland.
authors.forename: Lea
authors.initials: L
authors.lastname: Bachmann
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology, ETH Zürich, CH-8093 Zürich, Switzerland.
authors.forename: Camilla
authors.initials: C
authors.lastname: Norrmén
authors.affiliation: Core Facility for Mass Spectrometry/Lipidomics, Center for Medical Research, Medical University of Graz, 8010 Graz, Austria, Omics Center Graz, 8010 Graz, Austria, and.
authors.forename: Martin
authors.initials: M
authors.lastname: Trötzmüller
authors.affiliation: Core Facility for Mass Spectrometry/Lipidomics, Center for Medical Research, Medical University of Graz, 8010 Graz, Austria, Omics Center Graz, 8010 Graz, Austria, and.
authors.forename: Harald
authors.initials: H
authors.lastname: Köfeler
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, ETH Zürich, CH-8093 Zürich, Switzerland, usuter@cell.biol.ethz.ch.
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D005260:Female; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: TSC1; TSC2; mTOR; myelin; oligodendrocytes; tuberous sclerosis