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Death receptor 6 negatively regulates oligodendrocyte survival, maturation and myelination

Nature Medicine volume 17, pages 816–821 (2011)Cite this article

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Abstract

Survival and differentiation of oligodendrocytes are important for the myelination of central nervous system (CNS) axons during development and crucial for myelin repair in CNS demyelinating diseases such as multiple sclerosis. Here we show that death receptor 6 (DR6) is a negative regulator of oligodendrocyte maturation. DR6 is expressed strongly in immature oligodendrocytes and weakly in mature myelin basic protein (MBP)-positive oligodendrocytes. Overexpression of DR6 in oligodendrocytes leads to caspase 3 (casp3) activation and cell death. Attenuation of DR6 function leads to enhanced oligodendrocyte maturation, myelination and downregulation of casp3. Treatment with a DR6 antagonist antibody promotes remyelination in both lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis (EAE) models. Consistent with the DR6 antagoinst antibody studies, DR6-null mice show enhanced remyelination in both demyelination models. These studies reveal a pivotal role for DR6 signaling in immature oligodendrocyte maturation and myelination that may provide new therapeutic avenues for the treatment of demyelination disorders such as multiple sclerosis.

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Figure 1: DR6 is expressed in oligodendrocytes.
Figure 2: DR6 antagonists promote A2B5+ OPC survival and differentiation.
Figure 3: Inhibition of DR6 promotes oligodendrocyte survival, maturation and myelination.
Figure 4: Antibody to DR6 promotes functional recovery and remyelination in the rat EAE model.
Figure 5: A DR6 antagonist promotes remyelination in brain slice cultures and in the LPC-induced spinal cord demyelination model.
Figure 6: Oligodendrocyte maturation and myelination in DR6-null mice.

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Authors and Affiliations

  1. Biogen Idec, Cambridge, Massachusetts, USA

    Sha Mi, Xinhua Lee, Yinghui Hu, Benxiu Ji, Zhaohui Shao, Weixing Yang, Guanrong Huang, Lee Walus, Kenneth Rhodes, Bang Jian Gong & R Blake Pepinsky

  2. Department of Neurosciences, Center for Translational Neuroscience, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

    Robert H Miller

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Contributions

S.M. supervised all experiments and wrote the paper. X.L., Y.H., B.J., Z.S., W.Y., G.H., L.W. and B.J.G. performed experiments. K.R. and R.B.P. provided helpful discussions, and R.H.M. and R.B.P. revised the paper.

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Correspondence to Sha Mi.

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Mi, S., Lee, X., Hu, Y. et al. Death receptor 6 negatively regulates oligodendrocyte survival, maturation and myelination. Nat Med 17, 816–821 (2011). https://doi.org/10.1038/nm.2373

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