Nature Neuroscience
8, 745 - 751 (2005)
Published online: 15 May 2005; | doi:10.1038/nn1460
LINGO-1 negatively regulates myelination by oligodendrocytesSha 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 Pepinsky11
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.
Correspondence should be addressed to Sha Mi sha.mi@biogenidec.comThe 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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