Journal
JOURNAL OF NEUROSCIENCE
Volume 37, Issue 31, Pages 7534-7546Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3454-16.2017
Keywords
adult OPCs; mTOR; NG2; remyelination; TSC
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Funding
- National Institute of Neurological Disorders and Stroke-National Institutes of Health [NS082203]
- National Multiple Sclerosis Society [RG5371-A-4]
- Department of Defense Tuberous Sclerosis Complex Research Program [TS093091]
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Although the mammalian target of rapamycin (mTOR) is an essential regulator of developmental oligodendrocyte differentiation and myelination, oligodendrocyte-specific deletion of tuberous sclerosis complex (TSC), a major upstream inhibitor of mTOR, surprisingly also leads to hypomyelination during CNS development. However, the function of TSC has not been studied in the context of remyelination. Here, we used the inducible Cre-lox system to study the function of TSC in the remyelination of a focal, lysolecithin-demyelinated lesion in adult male mice. Using two different mouse models in which Tsc1 is deleted by Cre expression in oligodendrocyte progenitor cells (OPCs) or in premyelinating oligodendrocytes, we reveal that deletion of Tsc1 affects oligodendroglia differently depending on the stage of the oligodendrocyte lineage. Tsc1 deletion from NG2(+) OPCs accelerated remyelination. Conversely, Tsc1 deletion from proteolipid protein (PLP)-positive oligodendrocytes slowed remyelination. Contrary to developmental myelination, there were no changes in OPC or oligodendrocyte numbers in either model. Our findings reveal a complex role for TSC in oligodendrocytes during remyelination in which the timing of Tsc1 deletion is a critical determinant of its effect on remyelination. Moreover, our findings suggest that TSC has different functions in developmental myelination and remyelination.
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