期刊
JOURNAL OF NEUROSCIENCE
卷 34, 期 25, 页码 8432-8448出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1105-14.2014
关键词
mTOR; myelin; oligodendrocytes; TSC1; TSC2; tuberous sclerosis
资金
- Marie Curie International Incoming Fellowship within the 7th European Community framework
- Swiss Federal Institute of Technology (ETH) fellowship
- Marie Curie Intra European Fellowship within the 7th European Community framework
- Swiss National Science Foundation
- National Center of Competence in Research Neural Plasticity and Repair.
The mammalian target of rapamycin (mTOR) pathway integrates multiple signals and regulates crucial cell functions via the molecular complexes mTORC1 and mTORC2. These complexes are functionally dependent on their raptor (mTORC1) or rictor (mTORC2) subunits. mTOR has been associated with oligodendrocyte differentiation and myelination downstream of the PI3K/Akt pathway, but the functional contributions of individual complexes are largely unknown. We show, by oligodendrocyte-specific genetic deletion of Rptor and/or Rictor in the mouse, that CNS myelination is mainly dependent on mTORC1 function, with minor mTORC2 contributions. Myelin-associated lipogenesis and protein gene regulation are strongly reliant on mTORC1. We found that also oligodendrocyte-specific overactivation of mTORC1, via ablation of tuberous sclerosis complex 1 (TSC1), causes hypomyelination characterized by downregulation of Akt signaling and lipogenic pathways. Our data demonstrate that a delicately balanced regulation of mTORC1 activation and action in oligodendrocytes is essential for CNS myelination, which has practical overtones for understanding CNS myelin disorders.
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