Function and regulation of heterotrimeric G proteins in ciliogenesis and pathobiology of neurodevelopmental disorders

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PROJECT SUMMARY Many components of G-protein-coupled receptor (GPCR) signaling including heterotrimeric G (abg) proteins localize to primary cilia and modulate their morphology. Although cilia defects and dysregulated G protein signaling are associated with neurodevelopmental disorders (NDDs), the mechanisms by which G proteins regulate cilia morphogenesis or the extent to which disruption of ciliary Ga signaling contributes to NDDs remain largely unknown. The overall objective for this proposal is to define the molecular mechanisms by which RIC-8 – a highly conserved GPCR-independent activator of Ga proteins – shapes cilia morphology in sensory neurons. The overarching hypothesis for this application is that RIC-8 is dynamically trafficked to sensory cilia and controls ciliogenesis by potentiating Ga signaling. This hypothesis will be tested by pursuing two specific aims. Under the first aim, in vivo protein interaction assays and genome editing approaches will be used to mechanistically define the functional role of the RIC-8-Gai/o axis in controlling cilia morphogenesis. For the second aim, a synergistic approach comprised of genetic, imaging and in vivo proteomic approaches will be applied to identify molecular regulators of RIC-8 ciliary transport and function in sensory neurons. The proposed research is innovative because it uses a comprehensive approach to define a novel cellular function of RIC-8- Gai/o signaling in neuronal development. The proposed research is significant because it is expected to establish a strong scientific framework for investigations into the molecular composition and functions of the ciliary RIC-8- Gai/o signaling network(s) in C. elegans and vertebrate models and to determine how altered Ga-protein signaling may contribute to neurodevelopmental disorders.