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.

Myelination and mTOR

“…The physiologically high mTORC1 activity before onset of myelination is likely to contribute to a transient halt of the SC differentiation program to allow completion of radial sorting of large axons by immature SCs before starting the process of myelination. Such a mechanism is consistent with the findings that radial sorting was accelerated in the presence of high mTORC1 activity, but impaired in the opposite case (Figlia et al, 2017; Norrmén et al, 2014). In addition, direct or indirect promotion of SC proliferation by high mTORC1 activity might contribute as a causative differentiation‐inhibitory factor (Beirowski et al, 2017; Figlia et al, 2017).…”

“…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.…”

“…Myelin lipids were also reduced upon deletion of Raptor (Lebrun‐Julien et al, 2014; Norrmén et al, 2014). This correlated with reduced expression or activation of the mTORC1‐regulated transcription factors SREBP1c and SREBP2.…”

“…Specifically, SREBP1c mRNA levels were decreased in the PNS, while SREBP2 mRNA levels were decreased only in the CNS. In SCs, but not in OLs, the transcription factor RXRγ was shown to be transcriptionally regulated by mTORC1 and to control, in turn, the transcription of SREBP1c downstream of mTORC1 (Lebrun‐Julien et al, 2014; Norrmén et al, 2014). Differently from other cell types (Düvel et al, 2010; Owen et al, 2012), the mTORC1 target S6K is probably not majorly involved in regulating SREBPs.…”

“…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)…”