Nature Neuroscience8, 745 - 751 (2005)
Published online: 15 May 2005; | doi:10.1038/nn1460
LINGO-1 negatively regulates myelination by oligodendrocytes
Sha Mi1, Robert H Miller2, Xinhua Lee1, Martin L Scott1, Svetlane Shulag-Morskaya1, Zhaohui Shao1, Jufang Chang3, Greg Thill1, Melissa Levesque1, Mingdi Zhang1, Cathy Hession1, Dinah Sah1, Bruce Trapp4, Zhigang He3, Vincent Jung1, John M McCoy1
& R Blake Pepinsky1
1
Department of Discovery Biology, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA.
2
Department of Neuroscience, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
3
Division of Neuroscience, Children's Hospital, Harvard Medical School, 320 Longwood Avenue, Boston, Massachusetts 02115, USA.
4
Department of Neuroscience, NC30, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
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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