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

Abstract

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.

The LKB1‐AMPK and mTORC1 Metabolic Signaling Networks in Schwann Cells Control Axon Integrity and Myelination

“…The characterization of the developmental nerve phenotypes in these mutants led to the surprising conclusion that mTORC1 activity clearly impedes myelin formation by promoting the proliferation of immature SCs and blocking SC differentiation during nerve development . This finding was subsequently confirmed by two other studies . Related molecular mechanisms for this function have been proposed including mTORC1‐mediated control of cell cycle regulators such as p27 Kip1 and Polo‐like kinases (PLKs), as well as the suppression of the transcription factor Egr2/Krox20 by hyperactive mTORC1‐S6K signaling .…”

“…Related molecular mechanisms for this function have been proposed including mTORC1‐mediated control of cell cycle regulators such as p27 Kip1 and Polo‐like kinases (PLKs), as well as the suppression of the transcription factor Egr2/Krox20 by hyperactive mTORC1‐S6K signaling . In stark contrast, induction of mTORC1 hyperactivity through TSC complex disruption in mature SCs that already established myelin, after nerve development is complete, led to aberrant myelin sheath overgrowth with no obvious impact on SC proliferation and differentiation . Thus, these studies unveiled two diametrical functions of mTORC1 in the SC lineage, both of which manifest depending on the differentiation context of SCs.…”

Fbxw7 is a critical regulator of Schwann cell myelinating potential

“…Although neither of the aberrant Fbxw7 mutant SC-axon interaction phenotypes have been previously described in vivo, several of the other phenotypes observed in Fbxw7 mutant nerves resemble phenotypes described in mutants where mTOR signaling is enhanced such as in Pten mutants [14] and constitutively active Akt mutants [15]. It is well documented, from these studies and others, that mTOR levels must be tightly regulated in SCs such that any type of manipulation results in defective PNS myelination [14,15,[19][20][21][22][23][24][25]. mTOR is a bona fide target of Fbxw7 in other contexts [16] and Fbxw7 was recently shown to control OL myelination through mTOR [7].…”

Novel Contribution of Secreted Amyloid-β Precursor Protein to White Matter Brain Enlargement in Autism Spectrum Disorder

“…It differentiates oligodendrocytes from OCPs. Interestingly, hyperactivation of oligodendrocytes after disruption of the TSC complex by deletion of TSC1 effects hypomyelination in the CNS and PNS (140, 141). Hypomyelination and decreased oligodendrocytes were also reported after deletion of TSC2 (142).…”