Genetic and molecular dissection of hair-cell function

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DESCRIPTION (provided by applicant): Deafness is one of the most common hereditary diseases, affecting one out of 1000 children. Human geneticists have made remarkable progress in identifying genes responsible for deafness, yet in many cases, we do not clearly understand either the function these genes or the pathology caused by the mutations. Moreover, our understanding of the sense of hearing lags behind our knowledge of other senses such as vision, taste, and touch. The molecules that directly mediate mechanotransduction in hair cells have yet to be been identified. In order to gain insight into the molecular basis of mechanotransduction and the function of deafness genes, we will take advantage of both forward and reverse genetics in the model vertebrate organism, the zebrafish. We have identified a total of 24 genes required for larval auditory and vestibular function from large scale mutagenesis screens, and have cloned four zebrafish genes thus far. Orthologues of all four genes are responsible for deafness in either humans or mice, demonstrating the relevance of our screen and a high degree of conservation of gene function. We will continue our cloning efforts by candidate or positional cloning approaches. In addition, our reverse genetic studies have proven fruitful, identifying a potential candidate gene for the mechanotransduction channel, NompC. As further evidence for a direct role in transduction, we will localize the NompC channel in zebrafish hair cells. One particular challenge will be to characterize and pinpoint the nature of the defects in our mutants or morpholino-injected animals. We will therefore create a transgenic calcium indicator line that will enable us to determine whether transduction, synaptic transmission, or central processing of auditory signals is affected in our auditory/vestibular mutants. The data from these experiments will help to increase our understanding of the biology of deafness genes and may lead to potential therapies for deafness patients.