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A RECURRENT <EM>TRIO</EM> GAIN-OF-FUNCTION VARIANT IMPACTS NEURODEVELOPMENT <EM>IN VIVO</EM>
Jeanne Bernardand 12 co-authors
Centre de Recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier, CNRS
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS06-09PM-098
Presentation
Date TBA
Board: PS06-09PM-098
Event Information
Poster Board
PS06-09PM-098
Poster
View posterAbstract
The RhoGEF TRIO plays a central role in neuronal development, by controlling actin cytoskeleton remodelling, primarily through the activation of the RAC1 GTPase. Numerous de novo TRIO mutations have been identified in individuals with severe neurodevelopmental disorders. In particular, one gain-of-function variant is frequently found in patients with TRIO-related severe intellectual disability (ID) and macrocephaly. We have previously proposed that this variant disrupts an intramolecular fold autoinhibiting TRIO, leading to hyperactivation of the RAC1 GTPase and perturbs axonal pathfinding in the zebrafish model. However, in vivo investigation of this effect in mammalian neurodevelopment was lacking. Here we present a novel knock-in mouse model for this specific gain-of-function mutation, and confirm the hyperactivation of RAC1 in vivo, in the mutant brain. Furthermore, the mutant mice present a phenotype reminiscent of the clinical features observed in patients, with general growth delay, macrocephaly, brain and skull dysmorphia, as well as behavioural problems including social interaction deficits, hyperactivity and memory deficits. Finally, we show that the TRIO gain-of-function variant has an impact on hippocampal morphology. In summary, by combining cellular, in vivo and behavioural data, we provide a compelling new mouse model that is relevant for mimicking the human disease and for understanding the consequences of a genetic variation in the TRIO gene on neurodevelopment.
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