Activation of the Mammalian Target of Rapamycin (mTOR) Is Essential for Oligodendrocyte Differentiation
Open accessAbstract
Although both extrinsic and intrinsic factors have been identified that orchestrate the differentiation and maturation of oligodendrocytes, less is known about the intracellular signaling pathways that control the overall commitment to differentiate. Here, we provide evidence that activation of the mammalian target of rapamycin (mTOR) is essential for oligodendrocyte differentiation. Specifically, mTOR regulates oligodendrocyte differentiation at the late progenitor to immature oligodendrocyte transition as assessed by the expression of stage specific antigens and myelin proteins including MBP and PLP. Furthermore, phosphorylation of mTOR on Ser 2448 correlates with myelination in the subcortical white matter of the developing brain. We demonstrate that mTOR exerts its effects on oligodendrocyte differentiation through two distinct signaling complexes, mTORC1 and mTORC2, defined by the presence of the adaptor proteins raptor and rictor, respectively. Disrupting mTOR complex formation via siRNA mediated knockdown of raptor or rictor significantly reduced myelin protein expression in vitro . However, mTORC2 alone controlled myelin gene expression at the mRNA level, whereas mTORC1 influenced MBP expression via an alternative mechanism. In addition, investigation of mTORC1 and mTORC2 targets revealed differential phosphorylation during oligodendrocyte differentiation. In OPC-DRG cocultures, inhibiting mTOR potently abrogated oligodendrocyte differentiation and reduced numbers of myelin segments. These data support the hypothesis that mTOR regulates commitment to oligodendrocyte differentiation before myelination.
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Oligodendrocyte autophagy, OPC differentiation, and myelination during development are all regulated by MTOR.
“In addition, oligodendrocyte autophagy, OPC differentiation, and myelination during development are all regulated by MTOR [445–447].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [447]
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- Authors
- Tyler, W. A., Gangoli, N., Gokina, P., Kim, H. A., Covey, M., Levison, S. W., & Wood, T. L.
- Affiliations
- Rutgers New Jersey Medical School (US)
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Wood, Teresa L.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-05-13
- Volume
- 29
- Issue
- 19
- Pages
- 6367-6378
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2827328
- OpenAlex
- W2040322783
- Cited by
- 263
- References
- 36
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 13 · 2023: 13 · 2022: 16 · 2021: 17 · 2020: 15 · 2019: 9 · 2018: 21 · 2017: 15 · 2016: 15 · 2015: 23 · 2014: 19 · 2013: 25 · 2012: 17
- FWCI
- 5.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH59950, R01MH059950)
- National Institute of Neurological Disorders and Stroke (NS056135, NS 37560, P30NS046593, R01NS037560, R01NS056135)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- mTOR, oligodendrocyte differentiation, mTORC1, mTORC2, raptors, Rictor, myelination, myelin basic protein, plasmalogens, oligodendrocyte precursor cells, white matter development, intracellular signaling, myelin gene expression
- MeSH terms
- Animals, Carrier Proteins, Cell Differentiation, Cells, Cultured, Myelin Basic Protein, Myelin Proteins, Nerve Tissue Proteins, Oligodendroglia, Phosphorylation, Protein Kinases, RNA, Messenger, Stem Cells, Transcription Factors, Gene Expression, Rats, Sprague-Dawley, Coculture Techniques, RNA, Small Interfering, Rats, Gene Knockdown Techniques, TOR Serine-Threonine Kinases
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