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.
Trio mediates netrin-1-induced Rac1 activation in axon outgrowth and guidance
Briancon-Marjollet, A.; Ghogha, A.; Nawabi, H.; Triki, I.; Auziol, C.; Fromont, S.; Piche, C.; Enslen, H.; Chebli, K.; Cloutier, J. F.; Castellani, V.; Debant, A.; Lamarche-Vane, N.
Molecular and Cellular Biology
2008-04 / vol 28 / pages 2314-2323
tyrosine kinase; neurite outgrowth; focal adhesion kinase; colorectal-cancer; c-elegans; commissural axons; exchange factor domains; growth cone guidance; rho-gef trio; signaling mechanisms