We are interested in identifying and studying mammalian genes that are involved in auditory function and development of the neuroepithelia of the inner ear. The molecular analysis of hearing loss mutations in the mouse is an ideal way of gaining access to such genes. This proposal focuses on one particular mouse mutation called Ames Waltzer (av). The av is a recessive mutation, which causes deafness and vestibular dysfunction associated with degeneration of the inner ear neuroepithelia. We identified the gene that harbors the av mutation, Pcdh15 (Protocadherin 15). Sequence analysis showed that Pcdh15 is a novel member of the cadherin super family. We recently showed that mutation in the human homologue of mouse Pcdh15 causes Usher syndrome type 1F and thus, establishing av mouse as a model for deafness in USH1F. Protocadherins represent a large family of non-classic cadherins that are structurally and functionally divergent from the classic cadherins. In higher vertebrates, based on expression data, protocadherins are thought to be involved in a variety of functions, including neural development, neural circuit formation, and formation of the synapse. The role of protocadherins in the peripheral sensory apparatus, such as the inner ear, is unknown. Ames waltzer mice provide genetic evidence that a protocadherins is required for inner ear development and function. In the proposed study, we plan to determine the function of Pcdh15 in the normal development of the inner ear neuroepithelia. Specifically, we will study temporal and spatial expression patterns of Pcdh15 to understand the role of this gene in the normal structure and function of the inner ear. By using in situ hybridization and immunohistochemical methods, we plan to determine the primary site of action of the gene product during the course of inner ear development. We also plan to conduct detailed morphological analysis (using electron microscopy) to correlate ultrastructure and the nature of the mutation in the different alleles of av. Additionally, we also plan to identify proteins that interact with the protein encoded by Pcdh15.
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