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The Journal of Neuroscience, May 13, 2009, 29(19):6367-6378; doi:10.1523/JNEUROSCI.0234-09.2009

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Development/Plasticity/Repair
Activation of the Mammalian Target of Rapamycin (mTOR) Is Essential for Oligodendrocyte Differentiation

William A. Tyler,¹ Nitish Gangoli,¹ Pradeepa Gokina,² Haesun A. Kim,² Matthew Covey,¹ Steven W. Levison,¹ and Teresa L. Wood¹

¹Department of Neurology & Neuroscience, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07101-1709, and ²Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102

Correspondence should be addressed to Teresa L. Wood, Department of Neurology & Neuroscience, University Hospital Cancer Center H1200, New Jersey Medical School/ University of Medicine and Dentistry of New Jersey, 205 South Orange Avenue, Newark, NJ 07101-1709. Email: woodte{at}umdnj.edu

Although both extrinsic and intrinsic factors have been identified that orchestrate the differentiation and maturation of oligodendrocytes, less 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 MBP and PLP. Furthermore, phosphorylation of mTOR on Ser 2448 correlates with myelination in the subcortical white matter of the developing brain. We 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. Disrupting mTOR complex formation via siRNA mediated knockdown of raptor or rictor significantly reduced myelin protein expression in vitro. However, mTORC2 alone controlled myelin gene expression at the mRNA level, whereas mTORC1 influenced MBP expression via an alternative mechanism. In addition, investigation of mTORC1 and mTORC2 targets revealed differential phosphorylation during oligodendrocyte differentiation. In OPC-DRG cocultures, inhibiting mTOR potently abrogated oligodendrocyte differentiation and reduced numbers of myelin segments. These data support the hypothesis that mTOR regulates commitment to oligodendrocyte differentiation before myelination.

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Received Jan. 15, 2009; revised March 22, 2009; accepted March 27, 2009.

Correspondence should be addressed to Teresa L. Wood, Department of Neurology & Neuroscience, University Hospital Cancer Center H1200, New Jersey Medical School/ University of Medicine and Dentistry of New Jersey, 205 South Orange Avenue, Newark, NJ 07101-1709. Email: woodte{at}umdnj.edu

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