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The Journal of Neuroscience, July 22, 2009, 29(29):9174-9185; doi:10.1523/JNEUROSCI.5942-08.2009

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Cellular/Molecular
An Integrin–Contactin Complex Regulates CNS Myelination by Differential Fyn Phosphorylation

Lisbeth Schmidt Laursen,¹ Colin W. Chan,² and Charles ffrench-Constant¹

¹Medical Research Council Centre for Regenerative Medicine and Multiple Sclerosis Society Translational Research Initiative, Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, EH16 4TJ Edinburgh, United Kingdom, and ²Department of Pathology, University of Cambridge, CB2 1QP Cambridge, United Kingdom

Correspondence should be addressed to Lisbeth Schmidt Laursen, Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ Edinburgh, UK. Email: ls.laursen{at}ed.ac.uk

The understanding of how adhesion molecules mediate the axon–glial interactions in the CNS that ensure target-dependent survival of oligodendrocytes and initiate myelination remains incomplete. Here, we investigate how signals from adhesion molecules can be integrated to regulate these initial steps of myelination. We first demonstrate that the Ig superfamily molecule contactin is associated in oligodendrocytes with integrins, extracellular matrix receptors that regulate target-dependent survival by amplification of growth factor signaling. This amplification is inhibited by small interfering RNA-mediated knockdown of contactin in oligodendrocytes. In contrast, the presence of L1-Fc, the extracellular portion of a contactin ligand expressed on axons, enhanced survival and additionally promoted myelination in cocultures of neurons and oligodendrocytes. We further demonstrate that the signals from contactin and integrin are integrated by differential phosphorylation of the Src family kinase Fyn. Integrin induced dephosphorylation of the inhibitory Tyr-531, whereas contactin increased phosphorylation of both Tyr-531 and the activating Tyr-420. The combined effect is an enhanced activity of Fyn and also a dynamic regulation of the phosphorylation/dephosphorylation balance of Fyn, as required for normal cell adhesion and spreading. We conclude, therefore, that a novel integrin/contactin complex coordinates signals from extracellular matrix and the axonal surface to regulate both oligodendrocyte survival and myelination by controlling Fyn activity.

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Received Dec. 12, 2008; revised April 20, 2009; accepted June 4, 2009.

Correspondence should be addressed to Lisbeth Schmidt Laursen, Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ Edinburgh, UK. Email: ls.laursen{at}ed.ac.uk

This article has been cited by other articles:

				P.-S. Wang, J. Wang, Z.-C. Xiao, and C. J. Pallen Protein-tyrosine Phosphatase {alpha} Acts as an Upstream Regulator of Fyn Signaling to Promote Oligodendrocyte Differentiation and Myelination J. Biol. Chem., November 27, 2009; 284(48): 33692 - 33702. [Abstract] [Full Text] [PDF]

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