The inner ear is a highly asymmetrical sensory structure with clearly defined anterior-posterior (A-P) and dorsal-ventral (D-V) axes. How these axes arise during embryonic development from a simple epithelium, the otic placode, and the genes involved in this patterning are almost completely unknown. Inner ear sensory organs (consisting of mechanosensory hair cells) are precisely positioned within the nonsensory membranous labyrinth and represent a small percentage of actual ear tissue. Their position and orientation are vital for normal function in balance and hearing. Any problems during the development of this complex structure would result in balance or hearing deficits. Our long-term goal is to determine the molecular signaling pathways necessary for inner ear patterning. Advances in vital dyes, intravital imaging and gene function assays in the African clawed frog, Xenopus laevis, as well as the ease with which embryological manipulations can be done, combine to offer us the unique opportunity to address our proposed specific aims (SA) and hypotheses (HYP) in living embryos and tadpoles. SA 1: Determine which regions of the inner ear placode or otocyst are required for normal patterning. HYP. Dorsal and/or ventral signals are necessary for normal A-P patterning of the inner ear. SA 2: Role of Hedgehog (Hh) signaling in the patterning of the developing inner ear. HYP. Hh signaling, after otic placode formation, is required for both A-P and ventral patterning of the inner ear. SA 3: Role of canonical Wnt signaling in the patterning of the developing inner ear. HYP. Wnt signaling, after otocyst formation, plays a role in A-P as well as D-V patterning of the inner ear. Lay Summary: The lack of regenerative potential of the developing inner ear in contrast to other sensory organs, such as the nose, may help explain why deafness is one of the more common birth defects. A key question is not just which molecules induce the formation of hair cells (specialized cells in the ear that transduce sound to electrical inputs for the brain to interpret) but more important for actual hearing and balance is the need to form and place these new hair cells in precise positions in the newly formed inner ear. This proposal will identify which molecules are necessary for putting these hair cells in the right place so they can function in hearing and balance. The frog inner ear is very similar to ours so it provides a good model for studying inner ear development. ? ? ?
