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.
MeSH terms
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Animals
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Cells, Cultured
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Central Nervous System / embryology*
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Central Nervous System / growth & development
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Central Nervous System / metabolism
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Coculture Techniques
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Down-Regulation / drug effects
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Down-Regulation / genetics*
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Gene Expression Regulation, Developmental / drug effects
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Gene Expression Regulation, Developmental / genetics
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Humans
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Membrane Proteins
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Mice
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Mice, Knockout
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Microscopy, Electron, Transmission
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Myelin Sheath / genetics
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Myelin Sheath / metabolism*
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Myelin Sheath / ultrastructure
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Myelin-Associated Glycoprotein / antagonists & inhibitors
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Myelin-Associated Glycoprotein / genetics*
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Myelin-Associated Glycoprotein / metabolism
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Nerve Fibers, Myelinated / drug effects
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Nerve Fibers, Myelinated / metabolism*
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Nerve Fibers, Myelinated / ultrastructure
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Nerve Tissue Proteins
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Oligodendroglia / drug effects
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Oligodendroglia / metabolism*
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Oligodendroglia / ultrastructure
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-fyn
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RNA Interference / drug effects
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RNA Interference / physiology
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Ranvier's Nodes / genetics
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Ranvier's Nodes / metabolism
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Ranvier's Nodes / ultrastructure
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Rats
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Rats, Long-Evans
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Receptors, Cell Surface / antagonists & inhibitors
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Receptors, Cell Surface / genetics*
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Receptors, Cell Surface / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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rhoA GTP-Binding Protein / metabolism
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src-Family Kinases / genetics
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src-Family Kinases / metabolism
Substances
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LINGO1 protein, human
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Membrane Proteins
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Myelin-Associated Glycoprotein
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Nerve Tissue Proteins
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Proto-Oncogene Proteins
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Receptors, Cell Surface
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FYN protein, human
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Fyn protein, mouse
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Fyn protein, rat
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Proto-Oncogene Proteins c-fyn
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src-Family Kinases
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rhoA GTP-Binding Protein