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Trio Mediates Netrin-1-Induced Rac1 Activation in Axon Outgrowth and Guidance

Anne Briançon-Marjollet,¹ Atefeh Ghogha,² Homaira Nawabi,³ Ibtissem Triki,² Camille Auziol,¹ Sylvie Fromont,¹ Chantal Piché,² Hervé Enslen,⁵ Karim Chebli,⁴ Jean-François Cloutier,⁶ Valérie Castellani,³ Anne Debant,^1,* and Nathalie Lamarche-Vane^2,*

CRBM, UMR-CNRS 5237, Université Montpellier I et II, IFR 122, Montpellier 34293, France,¹ McGill University, Department of Anatomy and Cell Biology, Montreal, Quebec, Canada H3A 2B2,² CGMC UMR-CNRS 5534, Université Claude Bernard Lyon 1, 69622 Villeurbanne, France,³ IGMM UMR-CNRS, Université Montpellier II, Montpellier 34293, France,⁴ Unité mixte de recherche Santé UMR-S536, INSERM, Institut du Fer à Moulin, 75005 Paris, France,⁵ Montreal Neurological Institute, McGill University, Department of Neurology and Neurosurgery, Montreal, Quebec, Canada H3A 2B4⁶

Received 6 June 2007/ Returned for modification 1 August 2007/ Accepted 7 January 2008

The chemotropic guidance cue netrin-1 promotes neurite outgrowth through its receptor Deleted in Colorectal Cancer (DCC) 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 toward 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.

Published ahead of print on 22 January 2008.

A.D. and N.L.-V. contributed equally to this work.