Dual function of the PI3K-Akt-mTORC1 axis in myelination of the peripheral nervous system

Abstract

Myelination is a biosynthetically demanding process in which mTORC1, the gatekeeper of anabolism, occupies a privileged regulatory position. We have shown previously that loss of mTORC1 function in Schwann cells (SCs) hampers myelination. Here, we genetically disrupted key inhibitory components upstream of mTORC1, TSC1 or PTEN, in mouse SC development, adult homeostasis, and nerve injury. Surprisingly, the resulting mTORC1 hyperactivity led to markedly delayed onset of both developmental myelination and remyelination after injury. However, if mTORC1 was hyperactivated after myelination onset, radial hypermyelination was observed. At early developmental stages, physiologically high PI3K-Akt-mTORC1 signaling suppresses expression of Krox20 (Egr2), the master regulator of PNS myelination. This effect is mediated by S6K and contributes to control mechanisms that keep SCs in a not-fully differentiated state to ensure proper timing of myelination initiation. An ensuing decline in mTORC1 activity is crucial to allow myelination to start, while remaining mTORC1 activity drives myelin growth.

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).…”

“…Downstream of mTORC1, S6K appears to be the responsible mediator by inhibiting transcriptionally Krox20 expression. Consistent with these findings, Krox20 levels were conversely upregulated in SC‐specific Raptor mutants and in SCs treated with rapamycin in vitro (Figlia et al, 2017). 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.…”

“…These results are in line with reports of abnormal white matter microstructure in the brain of patients with tuberous sclerosis, a systemic disorder caused by loss‐of‐function mutations of TSC1 or TSC2 (Ercan et al, 2017). Additionally, after the delayed onset of myelination upon deletion of TSC1 in the PNS as discussed above, mutant SCs produced thinner myelin sheaths (Figlia et al, 2017). At least five mechanisms might account for these paradoxical results.…”

“…First, under normal physiological conditions, mTORC1 activity in SCs is high prior to the onset of myelination and declines to lower levels as cells progress from the promyelinating stage further (Beirowski, Wong, Babetto, & Milbrandt, 2017; Figlia, Norrmen, Pereira, Gerber, & Suter, 2017; Heller et al, 2014). Second, mTORC1 hyperactivation due to SC‐specific deletion of TSC1 or the negative regulator of PI3K‐Akt signaling PTEN delayed onset of myelination (Beirowski et al, 2017; Figlia et al, 2017), while even higher mTORC1 activity following deletion of TSC2 persistently arrested onset of myelination (Beirowski et al, 2017). The physiological decline in mTORC1 activity is therefore required to allow onset of SC myelination.…”

“…The physiological decline in mTORC1 activity is therefore required to allow onset of SC myelination. On the molecular level, aberrantly high mTORC1 signaling impaired the timely upregulation of Krox20 (Egr2) expression (Figlia et al, 2017), the master transcription factor required for the onset of PNS myelination (Svaren & Meijer, 2008; Topilko et al, 1994). Downstream of mTORC1, S6K appears to be the responsible mediator by inhibiting transcriptionally Krox20 expression.…”