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"mTOR: A Key Regulator of Myelination in the CNS"

by
Stacey Wahl
Integrative Neurosciences Program
B.A. 2007, University of Delaware


Thesis Advisor: Teresa L. Wood, Ph.D.
Professor
Department of Neurology and Neurosciences

Tuesday, February 25, 2014
10:00 A.M., Cancer Center G-1196


Abstract

Oligodendrocytes are macroglial cells of the central nervous system that produce a lipid rich membrane called myelin. This myelin ensheathes axons and promotes fast neuronal conduction. Oligodendrocytes develop from progenitor cells generated in the neural tube. The specification of oligodendrocyte progenitors and their subsequent differentiation to mature into myelinating oligodendrocytes is regulated by extrinsic signals like growth factors. Several growth factors have been identified that promote specification, proliferation, differentiation, and myelination. These extrinsic signals converge on intracellular signaling pathways such as the PI3K/Akt pathway, which has demonstrated functions in myelination. A key downstream regulator of this pathway, mammalian target of rapamycin (mTOR) is necessary for oligodendrocyte differentiation and myelination in vitro (Tyler et al., 2009).
Here, we provide evidence that mTOR is necessary for oligodendrocyte differentiation, the initiation and the extent of myelination in spinal cord of mice. Interestingly, mTOR has a less marked effect in the brain, but does regulate myelin protein expression. Further, we identify novel targets of mTOR and show that its effects on the differentiation program are through a variety processes including lipid biosynthesis, cytoskeletal protein expression, and transcription factor regulation. Finally, we investigate a mechanism of mTOR action in vitro and in vivo. We demonstrate that mTOR negatively regulates bone morphogenetic protein (BMP) signaling, a well-studied signaling pathway that inhibits oligodendrocyte differentiation. mTOR regulates BMP signaling by promoting expression of SIP1, an inhibitor of BMP. This is the first evidence of interaction between mTOR and BMP signaling in oligodendrocytes. Taken together, these studies show the importance of mTOR for oligodendrocyte differentiation and myelination in vivo and identify a novel target of mTOR-signaling in oligodendrocytes.


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