Genetic Analysis of the Induction and Morphogenesis of the Inner Ear

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DESCRIPTION (provided by applicant): Development of the inner ear begins when two regions of ectoderm on either side of the embryonic hindbrain form thickened patches of epithelium called the otic placodes. All of the cell types that compose the membranous inner ear, including the mechanosensory hair cells and the neurons that innervate them, are descendents of cells in the otic placode. Consequently, any perturbations in formation of the otic placode can have severe consequences on the formation and function of the inner ear. Furthermore, it is estimated that up to 39% of cases of congenital hearing and balance disorders are associated with malformation of the inner ear. The long-term goal of this project is to understand the molecular pathways required for induction of the otic placode, which should enhance our understanding of those congenital hearing and balance disorders associated with inner ear malformation. Here we propose a genetic approach to elucidate the role of the Sprouty family of antagonists of receptor tyrosine kinase signaling, including Fibroblast Growth Factor (FGF) signaling, in otic placode induction. The specific aims of this proposal are: Aim 1) To analyze the redundant functions of the Spry1 and Spry2 genes during otic placode induction and to test the hypothesis that Spry1 and Spry2 function redundantly to limit the range of FGF signaling during induction of the otic placode. Aim 2) To test the hypothesis that Spry1 and Spry2 function redundantly at an early step in otic placode induction, and that other signaling pathways that contribute to otic placode induction will be misregulated in the absence of both Spry1 and Spry2 gene function. Aim 3) To determine the gene-sufficiency of the individual Spry1 and Spry2 genes during otic placode induction and to test the hypothesis that the tissue-specific expression of Spry1 and Spry2 is critical for proper induction of the otic placode.