Netrin requires focal adhesion kinase and Src family kinases for axon outgrowth and attraction

Nat Neurosci. 2004 Nov;7(11):1222-32. doi: 10.1038/nn1331. Epub 2004 Oct 17.

Abstract

Although netrins are an important family of neuronal guidance proteins, intracellular mechanisms that mediate netrin function are not well understood. Here we show that netrin-1 induces tyrosine phosphorylation of proteins including focal adhesion kinase (FAK) and the Src family kinase Fyn. Blockers of Src family kinases inhibited FAK phosphorylation and axon outgrowth and attraction by netrin. Dominant-negative FAK and Fyn mutants inhibited the attractive turning response to netrin. Axon outgrowth and attraction induced by netrin-1 were significantly reduced in neurons lacking the FAK gene. Our results show the biochemical and functional links between netrin, a prototypical neuronal guidance cue, and FAK, a central player in intracellular signaling that is crucial for cell migration.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Bromodeoxyuridine / metabolism
  • Cell Count / methods
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Size
  • Ganciclovir / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Glial Fibrillary Acidic Protein / genetics
  • Glial Fibrillary Acidic Protein / metabolism*
  • Green Fluorescent Proteins / metabolism
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Immunohistochemistry / methods
  • Integrases / metabolism
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism
  • Neural Cell Adhesion Molecule L1 / metabolism
  • Neuroglia / physiology*
  • Neurons / physiology*
  • Neuropeptides / metabolism
  • Olfactory Bulb / cytology
  • Olfactory Bulb / drug effects
  • Olfactory Bulb / metabolism
  • Phosphopyruvate Hydratase / metabolism
  • Prosencephalon / cytology*
  • Prosencephalon / drug effects
  • Prosencephalon / physiology
  • Sialic Acids / metabolism
  • Stem Cells / drug effects
  • Stem Cells / physiology*
  • Thymidine Kinase / genetics
  • Tubulin / metabolism
  • beta-Galactosidase / metabolism

Substances

  • Glial Fibrillary Acidic Protein
  • Microtubule-Associated Proteins
  • Neural Cell Adhesion Molecule L1
  • Neuropeptides
  • Sialic Acids
  • Tubulin
  • beta3 tubulin, mouse
  • doublecortin protein
  • polysialyl neural cell adhesion molecule
  • Green Fluorescent Proteins
  • Thymidine Kinase
  • Cre recombinase
  • Integrases
  • beta-Galactosidase
  • Phosphopyruvate Hydratase
  • Bromodeoxyuridine
  • Ganciclovir