title: Lck tyrosine kinase mediates β1-integrin signalling to regulate Schwann cell migration and myelination.
abstract: The interaction between laminin and β1-integrin on the surface of Schwann cells regulates Schwann cell proliferation, maturation and differentiation. However, the signalling mediators that fine-tune these outcomes are not fully elucidated. Here we show that lymphoid cell kinase is the crucial effector of β1-integrin signalling in Schwann cells. Lymphoid cell kinase is activated after laminin treatment of Schwann cells, while downregulation of β1-integrin with short interfering RNAs inhibits lymphoid cell kinase phosphorylation. Treatment of Schwann cells with a selective lymphoid cell kinase inhibitor reveals a pathway that involves paxillin and CrkII, which ultimately elevates Rac-GTP levels to induce radial lamellipodia formation. Inhibition of lymphoid cell kinase in Schwann cell-dorsal root ganglion cocultures and dorsal root ganglions from Lck(-/-) mice show a reduction of Schwann cell longitudinal migration, reduced myelin formation and internode length. Finally, Lck(-/-) mice exhibit delays in myelination, thinner myelin with abnormal g-ratios and aberrant myelin outfoldings. Our data implicate lymphoid cell kinase as a major regulator of cytoskeletal dynamics, migration and myelination in the peripheral nervous system.
authors.affiliation: Molecular Neuroscience Laboratory, Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Ness
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Snyder
authors.forename: Nikos
authors.initials: N
authors.lastname: Tapinos
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D018920:Coculture Techniques; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D007797:Laminin / Q000494:pharmacology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D050737:Proto-Oncogene Proteins c-crk / Q000378:metabolism; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D012583:Schwann Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D015398:Signal Transduction / Q000187:drug effects; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D019012:Integrin beta1; D007797:Laminin; D027701:Organic Cation Transport Proteins; D051419:Paxillin; D050737:Proto-Oncogene Proteins c-crk; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D020744:rac GTP-Binding Proteins