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

• Published in: Development (Cambridge) Vol. 145; no. 19
• Main Authors: Backer, Stéphanie, Lokmane, Ludmilla, Landragin, Camille, Deck, Marie, Garel, Sonia, Bloch-Gallego, Evelyne
• Format: Journal Article
• Language: English
• Published: England Company of Biologists 2018
• Subjects: Animals; Axon Guidance; Axons - metabolism; Body Patterning; Embryo, Mammalian - cytology; Fibroblasts - metabolism; Gene Expression Regulation, Developmental; Growth Cones - metabolism; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Life Sciences; Mice, Knockout; Models, Biological; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurobiology; Neurons - metabolism; Neurons and Cognition; Phosphoproteins - genetics; Phosphoproteins - metabolism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; rhoA GTP-Binding Protein - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Telencephalon - embryology; Telencephalon - metabolism; Thalamus - embryology; Thalamus - metabolism; Embryo; Neuron; Mouse; Migration; Slit2; Thalamocortical; Corridor cells; Axon guidance; Rho GTPase; Trio GEF; RhoA
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.153692

Trio, a member of the Dbl family of guanine nucleotide exchange factors, activates Rac1 downstream of netrin 1/DCC signalling in axon outgrowth and guidance. Although 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 mutant mouse embryos. We next studied the development of the ventral telencephalon and thalamocortical axons, which have been previously shown to be controlled by Slit2. Remarkably, this analysis revealed that knockout (KO) mice show phenotypes that bear strong similarities to the ones that have been reported in 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, highlighting its role in multiple guidance pathways as well as in biological functions of importance for a factor involved in human brain disorders.