Identification and characterization of novel functions for the Usher proteins in the inner ear

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ABSTRACT. An organism’s perception of its surrounding environment depends on the sensory function. Neurosensory cells from the inner ear are involved in key biological processes associated with hearing and balance. To be able to achieve their function these cells depend on a complex array of membrane receptors, ion channels, and signaling molecules that are concentrated at extremely sophisticated structures positioned at the apical (hair cell bundle and kinocilium) and basal (ribbon synapses) poles. Disruption of this network due, for example, to mutations, results in morphological and functional abnormalities and forms the bases of many human genetic disorders. This proposal is focused on studying the role of the Pcdh15-Itga8 (Protocadherin-15-Integrin alpha8) complex during hair cell (HC) development and function, and the downstream signaling pathways activated by it. Our recently published work and preliminary data suggest that the absence of Pcdh15-Itga8 complex results in HC bundle abnormalities, increase the number of outer hair cells, and alterations in the Rhoa-ERM(Ezrin-Radixin-Moesin)-Yap signaling cascade. Moreover, Itga8 hair cell-specific conditional knockout mice have progressive hearing loss and sensibility to noise exposure. Based on this information, our central hypothesis is that during inner ear development, environmental cues activate the Itga8-Pcdh15 complex resulting in the modulation of cytoskeletal elements that will activate downstream signaling cascades. Lack of the complex results in inner ear abnormalities that over time can cause progressive hearing loss. We will test this hypothesis with two specific aims. In the first aim, we will identify the environmental cues that lead to Pcdh15-Itga8 activation and the formation of cytoskeletal structures. We will also identify and characterize the complex’s molecular targets. In the second aim, we will investigate the contribution of supporting cells and spiral ganglion neurons to the Pcdh15-Itga8 complex phenotype and the sensibility to noise. Collectively the studies proposed here will clarify the functional role(s) for the Pcdh15-Itga8 complex during organ of Corti development, introducing a direct functional link between Usher syndrome and an integrin-downstream signaling cascade.