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

Nat Commun. 2013;4:1912. doi: 10.1038/ncomms2928.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / drug effects
  • Axons / metabolism
  • Cell Movement* / drug effects
  • Coculture Techniques
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / metabolism
  • Humans
  • Integrin beta1 / metabolism*
  • Laminin / pharmacology
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Myelin Sheath / drug effects
  • Myelin Sheath / metabolism*
  • Organic Cation Transport Proteins / metabolism
  • Paxillin / metabolism
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins c-crk / metabolism
  • Pseudopodia / drug effects
  • Pseudopodia / metabolism
  • Rats
  • Schwann Cells / cytology*
  • Schwann Cells / drug effects
  • Schwann Cells / enzymology*
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / metabolism
  • Sciatic Nerve / pathology
  • Sciatic Nerve / ultrastructure
  • Signal Transduction* / drug effects
  • rac GTP-Binding Proteins / metabolism

Substances

  • Integrin beta1
  • Laminin
  • Organic Cation Transport Proteins
  • Paxillin
  • Proto-Oncogene Proteins c-crk
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • rac GTP-Binding Proteins