Oligodendrocytes envelop axons with a myelin sheath in the central nervous system to facilitate action potential conduction. The establishment of axon myelination during development involves oligodendrocyte proliferation, differentiation, and production of myelin. The intracellular signaling mechanisms governing this process are only beginning to be elucidated. Previous data in our laboratory demonstrated mammalian target of rapamycin (mTOR) as essential for oligodendrocyte differentiation. mTOR, a downstream target of PI3K/Akt, regulates cell growth and proliferation in a number of cell types through complexes with adaptor proteins raptor (mTORC1) or rictor (mTORC2). mTORC1 and mTORC2 are present in oligodendrocyte progenitors and previous data indicate different functions for each complex during differentiation. My hypothesis is that the two mTOR complexes have essential and distinct functions during oligodendrocyte differentiation and that mTOR signaling is essential for remyelination as well as developmental myelination. Through the use of siRNA knockdown of complex specific proteins in primary oligodendrocyte cultures the effects of knockdowns of mTORC1 and mTORC2 will be characterized in vitro. Bigenic mice carrying floxed-mTOR and either a CNP-Cre transgene or an inducible PLP-Cre transgene will be created for oligodendrocyte specific knockdown of mTOR in vivo. These systems will be used to investigate the effects of specific deletion of mTOR on differentiation and myelination. Completion of these studies will elucidate how mTOR functions in oligodendrocyte differentiation, myelination and remyelination in vivo.
The first aim will investigate the role of mTORC2 in the regulation of transcription factors integral to the differentiation process.
Aim 2 will assess mTORC2 regulation of the cytoskeleton and process outgrowth.
Aim 3 will utilize in vivo models to determine the effects of mTOR knockdown on differentiation and myelination during development and following a demyelinating injury. Oligodendrocyte differentiation is disrupted in neonatal hypoxia-ischemia and in Multiple Sclerosis, illustrating a need for a detailed understanding of the mechanistic processes involved. These studies will further the understanding of oligodendrocyte differentiation and provide targets to pursue for therapeutic treatments of neuropathologies that impact oligodendrocytes and myelin formation.
This application proposes to determine the role of mTOR signaling in oligodendrocyte differentiation and production of myelin. Myelin wrapping of axons is essential for their conductance and is disrupted or damaged in neonatal hypoxia-ischemia and in multiple sclerosis. Understanding the effects of mTOR will provide targets for therapeutic treatment to enhance oligodendrocyte differentiation and promote remyelination in these central nervous system pathologies.
|Wahl, Stacey E; McLane, Lauren E; Bercury, Kathryn K et al. (2014) Mammalian target of rapamycin promotes oligodendrocyte differentiation, initiation and extent of CNS myelination. J Neurosci 34:4453-65|
|Wood, Teresa L; Bercury, Kathryn K; Cifelli, Stacey E et al. (2013) mTOR: a link from the extracellular milieu to transcriptional regulation of oligodendrocyte development. ASN Neuro 5:e00108|