Lck tyrosine kinase mediates β1-integrin signalling to regulate Schwann cell migration and myelination

Abstract

Schwan cells ensheath and insulate axons, enabling efficient transmission of action potentials. Ness and colleagues study the role of the kinase Lck in Schwan cells, and find that Lck signalling regulates cell migration, axonal sorting and myelin thickness. 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.