Balanced mTORC1 activity in oligodendrocytes is required for accurate CNS myelination.
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.
['Lebrun-Julien|Frédéric|F|', 'Bachmann|Lea|L|', 'Norrmén|Camilla|C|', 'Trötzmüller|Martin|M|', 'Köfeler|Harald|H|', 'Rüegg|Markus A|MA|', 'Hall|Michael N|MN|', 'Suter|Ueli|U|']
D000818:Animals D002490:Central Nervous System D005260:Female D008297:Male D000076222:Mechanistic Target of Rapamycin Complex 1 D051379:Mice D018345:Mice, Knockout D008822:Mice, Transgenic D046912:Multiprotein Complexes D009413:Nerve Fibers, Myelinated D009836:Oligodendroglia D013116:Spinal Cord D058570:TOR Serine-Threonine Kinases
oligodendrocytes myelin mTOR tuberous sclerosis TSC1 TSC2