Regulation of PERK–eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes

Jiang, Minqing; Liu, Lei; He, Xuelian; Wang, Haibo; Lin, Wensheng; Wang, Huimin; Yoon, Sung Ok; Wood, Teresa L.; Lu, Qiumin

doi:10.1038/ncomms12185

Cited by 47 publications

(55 citation statements)

References 72 publications

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“…This finding suggests that mTORC1 hyperactivity during adulthood in these mutants contributes to the pathologically redundant myelin. Inactivation of TSC1 or TSC2 in oligodendrocyte precursor cells causes reduced myelination in the CNS (37)(38)(39), with similarities to the SC lineage deficits observed herein (38,39). Our finding that TSC1/2 complex disruption in developing SCs promotes proliferation and suppresses differentiation has recent precedents in nonglial cell types (40)(41)(42).…”

Section: Discussionsupporting

confidence: 68%

mTORC1 promotes proliferation of immature Schwann cells and myelin growth of differentiated Schwann cells

Beirowski

Wong

Babetto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The myelination of axons in peripheral nerves requires precisely coordinated proliferation and differentiation of Schwann cells (SCs). We found that the activity of the mechanistic target of rapamycin complex 1 (mTORC1), a key signaling hub for the regulation of cellular growth and proliferation, is progressively extinguished as SCs differentiate during nerve development. To study the effects of different levels of sustained mTORC1 hyperactivity in the SC lineage, we disrupted negative regulators of mTORC1, including TSC2 or TSC1, in developing SCs of mutant mice. Surprisingly, the phenotypes ranged from arrested myelination in nerve development to focal hypermyelination in adulthood, depending on the level and timing of mTORC1 hyperactivity. For example, mice lacking TSC2 in developing SCs displayed hyperproliferation of undifferentiated SCs incompatible with normal myelination. However, these defects and myelination could be rescued by pharmacological mTORC1 inhibition. The subsequent reconstitution of SC mTORC1 hyperactivity in adult animals resulted in focal hypermyelination. Together our data suggest a model in which high mTORC1 activity promotes proliferation of immature SCs and antagonizes SC differentiation during nerve development. Down-regulation of mTORC1 activity is required for terminal SC differentiation and subsequent initiation of myelination. In distinction to this developmental role, excessive SC mTORC1 activity stimulates myelin growth, even overgrowth, in adulthood. Thus, our work delineates two distinct functions of mTORC1 in the SC lineage essential for proper nerve development and myelination. Moreover, our studies show that SCs retain their plasticity to myelinate and remodel myelin via mTORC1 throughout life.

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Section: Discussionsupporting

confidence: 68%

mTORC1 promotes proliferation of immature Schwann cells and myelin growth of differentiated Schwann cells

Beirowski

Wong

Babetto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…However, studies aimed at examining the consequences of increased mTORC1 activity, predicted to augment myelin growth, have yielded conflicting results. Overexpression of constitutively active Akt or hyperactivation of the PI3K-Akt pathway by deletion of PTEN in OLs caused hypermyelination ( Flores et al, 2008 ; Goebbels et al, 2010 ), while deleting TSC1 was detrimental to OL myelination ( Jiang et al, 2016 ; Lebrun-Julien et al, 2014 ). In SCs, hyperactivation of the PI3K-Akt pathway with various approaches did not lead to univocal results ( Cotter et al, 2010 ; Domènech-Estévez et al, 2016 ; Flores et al, 2008 ; Goebbels et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

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

Figlia

Norrmén

Pereira

et al. 2017

eLife

132

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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.

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“…Our data support the notion that the TSC1-mTOR signaling pathway In the central nervous system, sustained activation of mTOR signaling leads to ER stress and oligodendrocyte cell death, whereas in peripheral nerves, despite the increase in ER stress responses (Supporting Information Figure S2), excessive mTOR signaling activation promotes proliferation of immature SCs unchecked by apoptosis. Although the molecular mechanisms underlying distinct phenotypes in the central and peripheral nervous systems remain to be elucidated, elevation of adaptive responses mediated by p-eIF2a (Jiang et al, 2016;Way et al, 2015) in Tsc1-mutant SCs (Supporting Information Figure S2) and strong upregulation of the SC proliferative program may contribute to SC survival.…”

Section: Tsc1 Ablation-induced Hypomyelination Is Dependent On Polomentioning

confidence: 99%

“…In contrast to the central nervous system, where sustained activation of mTOR in oligodendrocyte progenitors in Tsc1 mutants leads to oligodendrocyte cell death and myelination defects with minimal impact on oligodendrocyte progenitor proliferation(Jiang et al, 2016), Tsc1 deletion in the SC lineage leads to an increase in SC proliferation and consequent arrest of the SC differentiation process without triggering substantial cell loss. These results suggest a distinct cell-type specific function of TSC1-mTOR signaling in oligodendrocyte and SC development.Differential responses with respect to cell survival and differentiation in oligodendrocytes and SCs following Tsc1-deletion suggest that the complex function of TSC1-mTOR is context-dependent.…”

mentioning

confidence: 90%

The TSC1‐mTOR‐PLK axis regulates the homeostatic switch from Schwann cell proliferation to myelination in a stage‐specific manner

Jiang

Rao

Wang

et al. 2018

Glia

Self Cite

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Proper peripheral myelination depends upon the balance between Schwann cell proliferation and differentiation programs. The serine/threonine kinase mTOR integrates various environmental cues to serve as a central regulator of cell growth, metabolism, and function. We report here that tuberous sclerosis complex 1 (TSC1), a negative regulator of mTOR activity, establishes a stage-dependent program for Schwann cell lineage progression and myelination by controlling cell proliferation and myelin homeostasis. Tsc1 ablation in Schwann cell progenitors in mice resulted in activation of mTOR signaling, and caused over-proliferation of Schwann cells and blocked their differentiation, leading to hypomyelination. Transcriptome profiling analysis revealed that mTOR activation in Tsc1 mutants resulted in upregulation of a polo-like kinase (PLK)-dependent pathway and cell cycle regulators. Attenuation of mTOR or pharmacological inhibition of polo-like kinases partially rescued hypomyelination caused by Tsc1 loss in the developing peripheral nerves. In contrast, deletion of Tsc1 in mature Schwann cells led to redundant and overgrown myelin sheaths in adult mice. Together, our findings indicate stage-specific functions for the TSC1-mTOR-PLK signaling axis in controlling the transition from proliferation to differentiation and myelin homeostasis during Schwann cell development.

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Regulation of PERK–eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes

Cited by 47 publications

References 72 publications

mTORC1 promotes proliferation of immature Schwann cells and myelin growth of differentiated Schwann cells

mTORC1 promotes proliferation of immature Schwann cells and myelin growth of differentiated Schwann cells

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

The TSC1‐mTOR‐PLK axis regulates the homeostatic switch from Schwann cell proliferation to myelination in a stage‐specific manner

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