The overall objective of our project is to understand the role of newly identified apical Planar Cell Polarity (PCP) signaling dependent on Gai-proteins during the maturation of the inner ear of mammals, in physiological and pathophysiological conditions. In the Western world, the proportion of the population that suffers from hearing loss is around 7 to 8%. Statistics collected from different countries show that out of 1,000 births, 1 to 1.5 will suffer profound hearing loss or deafness. Because the mechanoreceptive hair cells which mediate the sensory transduction in the inner ear can be injured or definitively lost after exposure to noise, otoxic drugs, or as part of normal aging, hearing losses are the fastest growing, and one of the most prevalent chronic conditions facing an aging population. Developing knowledge on the genetic and molecular bases of auditory cells differentiation that could guide strategies for regeneration and protection has the potential to lead to the establishment of new tools for prognosis and diagnosis of deafness, but also has the potential to open new avenue of research for inner ear pathologies in the hope to explore opportunities for preventive and therapeutic interventions. Recently, we have identified a new PCP signaling pathway, which we called G-protein-dependent PCP signaling (Ezan et al., 2013).During the course of this original study, we observed that in later stages of maturation, the hair bundles topping the hair cells appeared malformed, shorter and fragmented in two of the studied mice mutants, suggesting the involvement of certain genes of this PCP pathway in the late maturation of the hair cells and more generally in hearing function. As a first step, our proposal will explore this hypothesis, notably through the use of transgenic mouse models and in particular via Cre-lox technology that will allow us to study the postnatal development of the inner ear, its maturation and its function, or disruption of function. As a second step, we will explore the hypothesis that the apical complex Crumbs controls the dynamic of tubulin and actin, at least in part via the recruitment of certain of the apical PCP signaling pathway. For this, we will build on a multidisciplinary and multi-model approach that will bring us the benefits of three species: Xenopus, mouse and Drosophila. The results of our project will lead to the identification of a new family of candidate genes for deafness, to the elucidation of the molecular mechanism leading to these deafnesses and to decipher new protein networks at the crossroads between the apico-basal polarity, the Planar Cell Polarity and the cilium.