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Mol. Cell. Biol. doi:10.1128/MCB.00998-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Trio mediates netrin-1-induced Rac1 activation in axon outgrowth and guidance

CRBM, UMR- CNRS 5237, Université Montpellier I et II, IFR 122, Montpellier 34293, France; McGill University, Department of Anatomy and Cell Biology, Montreal, Quebec, Canada H3A 2B2; CGMC UMR-CNRS 5534, Université Claude Bernard Lyon1, 69622 Villeurbanne, France; IGMM UMR-CNRS, Université Montpellier II, Montpellier 34293, France; Unité mixte de recherche Santé UMR-S536, INSERM, Institut du Fer à Moulin, 75005 Paris, France; Montreal Neurological Institute, McGill University, Dept. of Neurology and Neurosurgery, Montreal, Quebec, Canada H3A 2B4

^* To whom correspondence should be addressed. Email: anne.debant{at}crbm.cnrs.fr. nathalie.lamarche{at}mcgill.ca.

	Abstract

The chemotropic guidance cue netrin-1 promotes neurite outgrowth through its receptor DCC (Deleted in Colorectal Cancer) via activation of Rac1. The guanine nucleotide exchange factor (GEF) linking netrin-1/DCC to Rac1 activation has not yet been identified. Here we show that the RhoGEF Trio mediates Rac1 activation in netrin-1 signaling. We found that Trio interacts with the netrin-1 receptor DCC in mouse embryonic brains, and that netrin-1-induced Rac1 activation in brain is impaired in the absence of Trio. Trio -/- cortical neurons fail to extend neurites in response to netrin-1, while they are able to respond to glutamate. Accordingly, netrin-1-induced commissural axon outgrowth is reduced in Trio -/- spinal cord explants and the guidance of commissural axons towards the floor plate is affected by the absence of Trio. The anterior commissure is absent in Trio-null embryos, and netrin-1/DCC-dependent axonal projections that form the internal capsule and the corpus callosum are defective in the mutants. Taken together, these findings establish Trio as a GEF that mediates netrin-1 signaling in axon outgrowth and guidance through its ability to activate Rac1.

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