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. Myelinassociated 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.

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.…”

“…Nevertheless, loss of only mTORC2 function had detectable consequences in the CNS. Deletion of Rictor in OL‐lineage cells caused a transient hypomyelination (Lebrun‐Julien et al, 2014) and transiently decreased expression of various myelin proteins (Bercury et al, 2014). Moreover, when both mTORC1 and mTORC2 functions were lost, more pronounced hypomyelination and molecular changes followed as compared with single disruption of mTORC1 (Lebrun‐Julien et al, 2014).…”

“…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).…”

“…Indeed, disruption of mTORC1 affected the levels of various myelin proteins. In particular, MBP was strikingly reduced without major changes in its mRNA level (Bercury et al, 2014; Lebrun‐Julien et al, 2014), indicating that translation of this and potentially other myelin proteins is specifically promoted by mTORC1. However, additional experimental confirmations are needed, together with insights into the underlying mechanisms.…”

“…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.…”