The vertebrate inner ear is a structurally complex organ consisting of fluid-filled ducts and toroidal canals protruding from a central vestibule. Congenital defects of inner ear morphogenesis can lead to deafness and balance disorders. This proposal aims to gain insight into the origins of congenital ear malformations by probing the molecular-genetic basis of otic vesicle morphogenesis. Our hypothesis is that gene expression domains subdivide the vertebrate otocyst into compartments that interact at boundaries to specify cell fate and pattern formation. We will fate map the chick and mouse otic cup by iontophoretic injection of fluorescent tracer dye. The fate maps will provide essential mechanistic information regarding the cellular movements responsible for conversion of the otic cup to an ovoid epithelial vesicle. This information will fill a critical void in the ear development field as it is not currently known how gene expression patterns at the placode stage correlate with those at the vesicle stage or beyond. In addition, the fate maps will provide a blueprint for the focal misexpression of a gene by retrovirus-mediated gene transfer. Our idea is that if precise boundaries of gene expression in the nascent otocyst are required for patterning the inner ear, then creation of temporally or spatially inappropriate foci of gene expression will likely perturb morphogenesis in a predictable way. A corollary goal of this proposal is to establish a mouse whole embryo culture model for studying early otic ontogeny. Experimental access to the ever-expanding list of natural and induced mutant mice would likely further our understanding of the genetic mechanisms that underlie inner ear morphogenesis and provide a basis for eliminating congenital deafness and balance disorders.
