Trio GEF mediates RhoA activation downstream of Slit2 and coordinates telencephalic wiring

Abstract

Trio, a member of the Dbl family of guanine nucleotide exchange factors (GEFs), activates Rac1 downstream of Netrin-1/DCC signalling in axon outgrowth and guidance. While it has been proposed that Trio also activates RhoA, the putative upstream factors remain unknown. Here, we show that Slit2 induces Trio-dependent RhoA activation, revealing a crosstalk between Slit and Trio/RhoA signalling. Consistently, we found that RhoA activity is hindered in vivo in trio mutant mouse embryos. We next studied the development of the ventral telencephalon and thalamocortical axons, previously shown to be controlled by Slit2. Remarkably, this analysis revealed that Trio KO shows phenotypes that bear strong similarities to the ones reported in Slit2 KO mice in both guidepost corridor cells and thalamocortical axon pathfinding in the ventral telencephalon. Taken together, our results show that Trio induces RhoA activation downstream of Slit2 and support a functional role in ensuring the proper positioning of both guidepost cells and a major axonal tract. Our study indicates a novel role for Trio in Slit2 signalling and forebrain wiring, thereby highlighting its role in multiple guidance pathways as well as in biological functions of importance for a factor involved in human brain disorders.