Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation.
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.
Forcet
Christelle
C
Apoptosis/Differentiation Laboratory label 'La Ligue' Molecular and Cellular Genetic Center, CNRS UMR 5534, University of Lyon, 69622 Villeurbanne, France.
Stein
Elke
E
Pays
Laurent
L
Corset
Véronique
V
Llambi
Fabien
F
Tessier-Lavigne
Marc
M
Mehlen
Patrick
P
D016475:3T3 Cells; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D048429:Cell Size / Q000187:drug effects; D046508:Culture Techniques; D000075389:DCC Receptor; D004268:DNA-Binding Proteins; D004789:Enzyme Activation / Q000187:drug effects; D017930:Genes, Reporter; D020439:Growth Cones / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology*; D000075388:Netrin-1; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D014981:Xenopus; D050807:ets-Domain Protein Elk-1
D015815:Cell Adhesion Molecules; D000075389:DCC Receptor; C501909:DCC protein, human; D004268:DNA-Binding Proteins; C501910:Dcc protein, mouse; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D050807:ets-Domain Protein Elk-1; D000075388:Netrin-1; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases