Lck tyrosine kinase mediates ?1-integrin signalling to regulate Schwann cell migration and myelination.

The interaction between laminin and ?1-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 ?1-integrin signalling in Schwann cells. Lymphoid cell kinase is activated after laminin treatment of Schwann cells, while downregulation of ?1-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. [ABSTRACT FROM AUTHOR]