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LINGO-1 negatively regulates myelination by oligodendrocytes

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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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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