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An integrin-contactin complex regulates CNS myelination by differential Fyn phosphorylation.

TitleAn integrin-contactin complex regulates CNS myelination by differential Fyn phosphorylation.
Publication TypeJournal Article
Year of Publication2009
AuthorsLaursen LS, Chan CW, ffrench-Constant C
JournalJ Neurosci
Date Published2009 Jul 22
KeywordsAnimals, Axons, Cell Adhesion Molecules, Neuronal, Cell Survival, Cells, Cultured, Coculture Techniques, Contactins, Extracellular Matrix, Gene Knockdown Techniques, Integrin alpha6beta1, Integrins, Models, Neurological, Myelin Sheath, Neurons, Oligodendroglia, Phosphorylation, Proto-Oncogene Proteins c-fyn, Rats, RNA, Small Interfering, Tyrosine

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.

Alternate JournalJ. Neurosci.
PubMed ID19625508
PubMed Central IDPMC4017644
Grant List089000 / / Wellcome Trust / United Kingdom
G0601744 / / Medical Research Council / United Kingdom
/ / Biotechnology and Biological Sciences Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom