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(1). In mammals, netrin-1 is a bifunctional cue, attracting some axons and repelling others(2-5). Deleted in colorectal cancer (Dcc) is a receptor for netrin-1 that mediates its chemoattractive effect on commissural axons(6,7), 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.