Role of the RhoGEF TRIO in neurodevelopmental diseases – TRIOTISM

Alterations in synaptic function are involved in neurological disorders such as autism spectrum disorders (ASD) and intellectual disability (ID). Rho GTPase signaling controls the morphogenesis of dendritic spines that support the synapses by regulating actin cytoskeleton dynamics. The Rho GTPase activator TRIO is a major regulator of axon outgrowth and guidance, and of synaptogenesis. TRIO controls actin cytoskeleton dynamics, and has been recently involved in microtubule (MT) dynamics. Deletion of TRIO in the mouse is embryonic lethal, showing that TRIO is an essential gene for mouse development.
Recent data have revealed de novo mutations in the TRIO gene in ID and ASD patients, suggesting that TRIO is a novel risk factor for these disorders. The general clinical phenotypes of the patients presenting TRIO mutations are rather heterogeneous. It is difficult so far to make genotype/phenotype correlations and to predict the effect of each missense change identified in patients on TRIO’s function in neuronal physiology. Our hypothesis is that missense mutations targeting different functional domains of TRIO are impacting TRIO’s neuronal function differently, leading to the phenotypic heterogeneity. Indeed, we obtained convincing preliminary data showing that mutations targeting different domains enhance or reduce TRIO activity. Interestingly, in both cases, mutations induce neurodevelopmental defects in patients suggesting that the activity of TRIO has to be tightly regulated.
The general goal of the project is to investigate how mutations in the TRIO gene contribute to neurodevelopmental diseases such as ID and ASD. We will test this hypothesis using complementary approaches such as human molecular and clinical genetics, combined to molecular and cell biology, and in vivo models (TRIO knock-in mutant mouse and zebrafish model). The specific objectives of the project are to: i) delineate “Trio phenotypes” to interpret the missense variants, especially in the context of diagnosis of ID and ASD; ii) evaluate the consequences of TRIO mutations on its cellular functions and in the etiology of these neurodevelopmental diseases using in vitro and in vivo approaches. This multidisciplinary project will associate four different teams with complementary expertise: i) Partner 1, coordinator of the project: Anne Debant (CRBM, Montpellier) expertise in Rho GTPase signalling, ii) Partner 2: Julie Perroy/Federica Bertaso (IGF, Montpellier), expertise in synapse physiology and in behavioral studies in mice. iii) Partner 3: Coralie Fassier (Institut de La Vision, Paris), expertise in neuronal development of the zebrafish; iv) Partner 4: Amélie Piton (IGBMC, Strasbourg & Strasbourg University Hospital), expertise in molecular genetics and diagnosis of ID/ASD.
This program represents a new exciting research avenue towards the understanding of the physiopathology of TRIO-associated disorders. Using complementary expertise, ranging from clinical and molecular genetics to basic research, we expect to determine how the mutations affect the development and the function of the nervous system and how they contribute to pathology. We are developing the first mouse model mimicking the human pathology of a patient harboring a missense mutation in the TRIO gene, which will be instrumental in determining how perturbations of TRIO activity can cause neurodevelopmental diseases such as ID or ASD.
The project will also have a strong impact on public health. The characterization of the effect of pathogenic mutations on TRIO neuronal function that will be done in the project will be very helpful to interpret the missense variants that will be identified in patients in the future. This will be of great help to improve the diagnosis of the patients and provide them adapted genetic counseling.