ACTIVATION OF THE MAMMALIAN TARGET OF RAPAMYCIN (MTOR) IS ESSENTIAL FOR OLIGODENDROCYTE DIFFERENTIATION
Open Access
- Author:
- Tyler, William Andrew
- Graduate Program:
- Cell and Molecular Biology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- May 25, 2007
- Committee Members:
- Teresa L Wood, Committee Chair/Co-Chair
Sarah Bronson, Committee Chair/Co-Chair
David A Antonetti, Committee Member
Steven W Levison, Committee Member
David J Carey, Committee Member - Keywords:
- oligodendrocyte
differentiation
mtor
rapamycin
progenitor
myelin - Abstract:
- Oligodendrocytes, the myelin producing glial cells of the central nervous system, arise from progenitor cells generated in the developing neural tube. The differentiation of oligodendrocyte progenitors into mature oligodendrocytes is a complex process that involves cell cycle exit and the coordinated expression of genes required for myelination. While both extrinsic and intrinsic factors have been identified that orchestrate the differentiation and maturation of oligodendrocytes, little 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 myelin basic protein (MBP) and proteolipid protein (PLP). Furthermore, phosphorylation of mTOR at Ser 2448 correlates with myelination in the subcortical white matter of the developing brain. We further 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. Disruption of TOR complex formation via siRNA mediated knockdown of raptor or rictor significantly reduced myelin protein expression in vitro. Investigation of mTORC1 and mTORC2 targets revealed differential phosphorylation during oligodendrocyte differentiation. Specifically, mTORC1 targets p70S6K1 and 4E-BP are phosphorylated during the initial phase of differentiation, while phosphorylation of the mTORC2 target Akt appears early but is sustained throughout differentiation. Finally, disruption of p70S6K1 reduces myelin protein expression suggesting that mTORC1 functions are mediated at least in part by p70S6K1. Taken together these data define mTOR signaling as an essential mediator of oligodendrocyte differentiation and myelination.