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LINGO-1 negatively regulates myelination by oligodendrocytes

Nature Neuroscience volume 8, pages 745–751 (2005)Cite this article

Abstract

The control of myelination by oligodendrocytes in the CNS is poorly understood. Here we show that LINGO-1 is an important negative regulator of this critical process. LINGO-1 is expressed in oligodendrocytes. Attenuation of its function by dominant-negative LINGO-1, LINGO-1 RNA-mediated interference (RNAi) or soluble human LINGO-1 (LINGO-1-Fc) leads to differentiation and increased myelination competence. Attenuation of LINGO-1 results in downregulation of RhoA activity, which has been implicated in oligodendrocyte differentiation. Conversely, overexpression of LINGO-1 leads to activation of RhoA and inhibition of oligodendrocyte differentiation and myelination. Treatment of oligodendrocyte and neuron cocultures with LINGO-1-Fc resulted in highly developed myelinated axons that have internodes and well-defined nodes of Ranvier. The contribution of LINGO-1 to myelination was verified in vivo through the analysis of LINGO-1 knockout mice. The ability to recapitulate CNS myelination in vitro using LINGO-1 antagonists and the in vivo effects seen in the LINGO-1 knockout indicate that LINGO-1 signaling may be critical for CNS myelination.

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Figure 1: LINGO-1 is expressed in oligodendrocytes.
Figure 2: LINGO-1 antagonists promote oligodendrocyte differentiation.
Figure 3: LINGO-1 antagonists regulate RhoA and Fyn.
Figure 4: LINGO-1 antagonists promote axonal myelination by oligodendrocytes.
Figure 5: Oligodendrocyte differentiation and myelination in LINGO-1 knockout mice.

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Acknowledgements

We thank J. Mason and other LINGO-1 team members and the research management team from Biogenidec for discussions.

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Authors and Affiliations

  1. Department of Discovery Biology, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Sha Mi, Xinhua Lee, Martin L Scott, Svetlane Shulag-Morskaya, Zhaohui Shao, Greg Thill, Melissa Levesque, Mingdi Zhang, Cathy Hession, Dinah Sah, Vincent Jung, John M McCoy & R Blake Pepinsky

  2. Department of Neuroscience, Case Western Reserve University School of Medicine, Cleveland, 44106, Ohio, USA

    Robert H Miller

  3. Division of Neuroscience, Children's Hospital, Harvard Medical School, 320 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Jufang Chang & Zhigang He

  4. Department of Neuroscience, NC30, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, 44195, Ohio, USA

    Bruce Trapp

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Correspondence to Sha Mi.

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Mi, S., Miller, R., Lee, X. et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat Neurosci 8, 745–751 (2005). https://doi.org/10.1038/nn1460

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