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Activation of the Mammalian Target of Rapamycin (mTOR) Is Essential for Oligodendrocyte Differentiation
- Source :
- The Journal of Neuroscience. 29:6367-6378
- Publication Year :
- 2009
- Publisher :
- Society for Neuroscience, 2009.
-
Abstract
- 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 expressionin 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.
- Subjects :
- Cellular differentiation
Gene Expression
Nerve Tissue Proteins
mTORC2
Article
Rats, Sprague-Dawley
Myelin
medicine
Animals
RNA, Messenger
Phosphorylation
RNA, Small Interfering
Cells, Cultured
PI3K/AKT/mTOR pathway
biology
Stem Cells
TOR Serine-Threonine Kinases
General Neuroscience
RPTOR
Oligodendrocyte differentiation
Cell Differentiation
Myelin Basic Protein
Coculture Techniques
Oligodendrocyte
Rats
Myelin basic protein
Cell biology
Oligodendroglia
medicine.anatomical_structure
Gene Knockdown Techniques
biology.protein
Carrier Proteins
Protein Kinases
Myelin Proteins
Transcription Factors
Subjects
Details
- ISSN :
- 15292401 and 02706474
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- The Journal of Neuroscience
- Accession number :
- edsair.doi.dedup.....83da6b43b76cfd9994a05617e0554eb1