Deafness is a major health problem. 1 in 800 children is born with hearing impairment and large parts of the aging population are afflicted by age-related hearing loss. Deafness can be caused by defects in hair cells, the mechanosensors for sound waves in the inner ear. The stereocilia of hair cells harbor mechanotransduction channels that open or close upon stereocilia deflection. The transduction channel and the molecules that regulate stereocilia movement are not known. This has prevented to determine the molecular mechanism of mechanotransduction and sound perception. The long term goal of our research is to understand the mechanisms that regulate mechanotransduction in hair cells, and the defects in this process that cause deafness. We propose here to study the role of cadherin 23 (CDH23) in hair cell function. We hypothesize that CDH23 assembles a transmembrane signalling complex that regulates stereocilia behavior. The hypothesis is based on the fact that mutations in CDH23 cause deafness, that cadherins in other cells assemble signalling complexes, and that stereocilia bundles in CDH23-deficient mice are disrupted. To test our hypothesis, we will: (i) determine the subcellular distribution of CDH23 in hair cells by immunohistochemistry; (ii) define its adhesive properties in cell adhesion assays; (iii) isolate by yeast-two-hybrid assays CDH23-interacting proteins; (iv) generate mouse line that carry defined mutations in CDH23 disrupting interactions with downstream effectors. Our preliminary data validate our hypothesis. The data show that CDH23 is localized to stereocilia, and binds to molecules implicated in signalling. We expect that transmembrane complexes connect stereocilia, their cytoskeleton and ion channels into a functional unit for sound perception. An understanding of this molecular machine will be important to develop rational strategies for therapeutic intervention in deafness.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-6 (01))
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Watson, Bracie
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Scripps Research Institute
La Jolla
United States
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