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

Elife. 2017 Sep 7;6:e29241. doi: 10.7554/eLife.29241.

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.

Keywords: cell biology; mTOR signaling; mouse; myelination; neuroscience; schwann cell.

MeSH terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myelin Sheath / metabolism*
  • PTEN Phosphohydrolase / metabolism
  • Peripheral Nervous System / cytology*
  • Peripheral Nervous System / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Schwann Cells / metabolism
  • Signal Transduction*
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins / metabolism

Substances

  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins
  • Phosphatidylinositol 3-Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • Pten protein, mouse

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.