Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation

Nature. 2002 May 23;417(6887):443-7. doi: 10.1038/nature748. Epub 2002 May 1.

Abstract

Neuronal growth cones are guided to their targets by attractive and repulsive guidance cues. In mammals, netrin-1 is a bifunctional cue, attracting some axons and repelling others. Deleted in colorectal cancer (Dcc) is a receptor for netrin-1 that mediates its chemoattractive effect on commissural axons, but the signalling mechanisms that transduce this effect are poorly understood. Here we show that Dcc activates mitogen-activated protein kinase (MAPK) signalling, by means of extracellular signal-regulated kinase (ERK)-1 and -2, on netrin-1 binding in both transfected cells and commissural neurons. This activation is associated with recruitment of ERK-1/2 to a Dcc receptor complex. Inhibition of ERK-1/2 antagonizes netrin-dependent axon outgrowth and orientation. Thus, activation of MAPK signalling through Dcc contributes to netrin signalling in axon growth and guidance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Cell Line
  • Cell Size / drug effects
  • Culture Techniques
  • DCC Receptor
  • DNA-Binding Proteins*
  • Enzyme Activation / drug effects
  • Genes, Reporter
  • Growth Cones / drug effects*
  • Growth Cones / enzymology*
  • Growth Cones / metabolism
  • Humans
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Nerve Growth Factors / metabolism
  • Nerve Growth Factors / pharmacology*
  • Netrin-1
  • Precipitin Tests
  • Proto-Oncogene Proteins / metabolism
  • Receptors, Cell Surface
  • Signal Transduction / drug effects
  • Spinal Cord / cytology
  • Spinal Cord / drug effects
  • Spinal Cord / growth & development
  • Transcription Factors*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Two-Hybrid System Techniques
  • Xenopus
  • ets-Domain Protein Elk-1

Substances

  • Cell Adhesion Molecules
  • DCC Receptor
  • DCC protein, human
  • DNA-Binding Proteins
  • Dcc protein, mouse
  • NTN1 protein, human
  • Nerve Growth Factors
  • Ntn1 protein, mouse
  • Proto-Oncogene Proteins
  • Receptors, Cell Surface
  • Transcription Factors
  • Tumor Suppressor Proteins
  • ets-Domain Protein Elk-1
  • Netrin-1
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases