The P.I. proposes to elucidate conserved mechanisms of vertebrate inner ear development through mutational analysis of the zebrafish, Danio rerio. Of particular interest are the molecular and cellular processes controlling the earliest stages of inner ear development, induction of the otic placode, morphogenesis of the otic vesicle, and differentiation of specific cell-types in sensory epithelia. A number of ENU-induced mutations affecting one or more of these events have been isolated and are under investigation. A variety of experiments are proposed to ascertain the means by which these mutations impede normal development of the inner ear. In addition, it is proposed to map the mutant genes with respect to molecular markers that can assist in the cloning of the affected genes. Finally, additional mutations affecting early development of the inner ear will be isolated and studied. Such systematic genetic analysis in zebrafish is likely to identify specific genes and cellular processes that operate in all vertebrates, including humans. A number of inherited and acquired diseases in humans disrupt one or both functions of the inner ear (hearing and balance) and can be quite debilitating. Determining how the inner ear develops will lead to a fuller understanding of how mature structures and functions of the inner ear are regulated. This in turn could lead to effective medical interventions to prevent, treat, or cure disorders of the inner ear.
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