Developmental origins of the inner ear sensory organs

House Research Institute, Los Angeles CA

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Abstract

DESCRIPTION (provided by applicant): The inner ear is a highly asymmetrical sensory structure with clearly defined anterior-posterior, dorsal- ventral, and medial-lateral 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. The placode undergoes a great deal of growth, morphogenesis, differentiation and selective cell death to form the adult inner ear. 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: Characterize an embryonic manipulation resulting in mirror image duplicated inner ears. Hyp. Half ablations along the anterior-posterior axis and not removal of greater or lesser amounts are necessary to generate mirror image duplications. SA 2: Role of Hedgehog (Hh) signaling in the patterning of the developing inner ear. Hyp. Hh signaling is involved in anterior-posterior patterning. SA 3: Role of Wnt signaling in the patterning of the developing inner ear. Hyp. Canonical Wnt signaling is involved in dorsal-ventral patterning while the noncanonical, Planar Cell Polarity (PCP), pathway is involved in morphogenesis and hair cell orientations. The lack of regenerative potential of the developing inner ear in contrast to other placodes, such as the olfactory, may help explain why deafness is one of the more common birth defects as opposed to those in other sensory placode derived structures. A key question is not just which molecules induce the formation of hair cells 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. [unreadable] [unreadable] [unreadable]