Mammalian Target of Rapamycin Promotes Oligodendrocyte Differentiation, Initiation and Extent of CNS Myelination

Abstract

Prior studies support a role for mammalian target of rapamycin (mTOR) signaling in oligodendrocyte differentiation and myelination. Here we use Cre-recombinase driven by the CNP promoter to generate a mouse line with oligodendrocyte-specific knockdown of mTOR (mTOR cKO) in the CNS. We provide evidence that mTOR is necessary for proper oligodendrocyte differentiation and myelination in the spinal cord. Specifically, the number of mature oligodendrocytes was reduced, and the initiation and extent of myelination were impaired during spinal cord development. Consistent with these data, myelin protein expression, including myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein, and myelin-associated glycoprotein, was delayed in the spinal cord. Hypomyelination of the spinal cord persisted into adulthood, as did the reduction in numbers of mature oligodendrocytes. In the cortex, the structure of myelin appeared normal during development and in the adult; however, myelin protein expression was delayed during development and was abnormal in the adult. Myelin basic protein was significantly reduced in all regions at postnatal day 25. These data demonstrate that mTOR promotes oligodendrocyte differentiation and CNS myelination in vivo and show that the requirement for mTOR varies by region with the spinal cord most dependent on mTOR.

mTOR in Brain Physiology and Pathologies

“…However, mice carrying a deletion of TSC1 or TSC2 also show a hypomyelination that is thought to be due to aberrant mTORC1 activation, because it is partially rescued by rapamycin administration (191). This suggests that a fine control of mTORC1 activity is required for proper oligodendrocyte differentiation and myelination (too little and too much are deleterious), as it has been recently confirmed in several independent reports (25,150,293). As in the CNS, suppression of mTOR in murine Schwann cells results in myelination retardation as well as thinner axonal diameters (265).…”

Myelination and mTOR

“…Ablation of Raptor or Rheb1 was used to suppress mTORC1 function (Bercury et al, 2014; Lebrun‐Julien et al, 2014; Norrmén et al, 2014; Zou et al, 2014), ablation of Rictor to suppress mTORC2 function (Bercury et al, 2014; Lebrun‐Julien et al, 2014; Norrmén et al, 2014), and ablation of mTOR itself to disrupt the functions of both complexes (Sherman et al, 2012; Wahl, McLane, Bercury, Macklin, & Wood, 2014). In each case, persistent hypomyelination was observed only in the absence of mTORC1 function, alone or in combination with loss of mTORC2.…”

“…Deletion of Raptor, Rheb1, or mTOR in OL‐lineage cells caused hypomyelination in the spinal cord and cerebellum, but not in the brain and optic nerve (Bercury et al, 2014; Lebrun‐Julien et al, 2014; Wahl et al, 2014; Zou et al, 2014). It was proposed that an increase in Mek‐Erk1/2 signaling selectively in the corpus callosum of Raptor mutants may compensate for the loss of mTORC1 function (Bercury et al, 2014).…”

“…The major outcomes of the loss‐ and gain‐of‐function studies on the roles of mTORC1 and the upstream PI3K‐Akt and Mek‐Erk1/2 pathways in PNS and CNS myelination are summarized (Beirowski et al, 2017; Bercury et al, 2014; Carson et al, 2015; Cotter et al, 2010; Domenech‐Estevez et al, 2016; Figlia et al, 2017; Flores et al, 2008; Fyffe‐Maricich, Karlo, Landreth, & Miller, 2011; Fyffe‐Maricich, Schott, Karl, Krasno, & Miller, 2013; Goebbels et al, 2010, 2012; Ishii, Furusho, & Bansal, 2013; Ishii, Furusho, Dupree, & Bansal, 2016; Jeffries et al, 2016; Jiang et al, 2016; Lebrun‐Julien et al, 2014; Napoli et al, 2012; Newbern et al, 2011; Norrmén et al, 2014; Sheean et al, 2014; Sherman et al, 2012; Wahl et al, 2014; Zou et al, 2011, 2014)…”

Perspective: The Potential Role of Essential Amino Acids and the Mechanistic Target of Rapamycin Complex 1 (mTORC1) Pathway in the Pathogenesis of Child Stunting

“…Myelin is composed primarily of lipids, such as cholesterol, sphingolipids, and glycerophospholipids, and a small proportion of proteins. In the central nervous system, myelination is mainly dependent on kinase Akt signaling through mTORC1 (97,98). In the peripheral nervous system, mTORC1 controls myelination and lipid synthesis by Schwann cells through nuclear receptor retinoic acid receptor g (RXRg) and SREBP (99).…”