The COUP-TFs are orphan nuclear receptors proven to play important roles in controlling diverse aspects of growth, development, differendation and homeostasis m several orgarisms. The COUP-TFs are regulators of gene expression and belong to the steroid thyroid hormone receptor superfamily of ligandactivated transcription factors. The pattern and timing of expression of an orphan nuclear receptor gene defines the sphere of direct influence of a putative hgand signaling pathway within its target tissues and cells. The spatial and temporal expression pattern of COUP-TEs during inner ear organogenesis suggest that they may play a critical role in reguladug processes that lead to the formation of a fUnctionaMnner ear. Indeed, COUPTFI loss-of-function mutants are deaf, having defects in development of the cochlea and sensory maculae of the ves6bule. This suggests that COUP-TFI is an essential gene for the development of both hearing and balance functions in the monse. To better understand the role of COUP-TFI in hearing and balance this grant will focus on the followmg aims. 1. Characterize defects in COUP-TFI mutants with respect to a detailed expression analysis of COUP-TFI during development and differentiation of inner ear structures and the brainstem auditory and vestibular nuclei. 2. Determine the mechanism of COUP-TFI action usmg chimeric embryo analysis to ascertain whether COUP-TFI acts in a cell-autonomous or non-autonomous manner in the ear. 3. Identify COUP-TFI downstream targets during inner ear development by subtraction library screens of cochlea and vestibule cDNA libraries. The completion of these aims will provide substantial insight on this novel regulator of itmer ear morphogenesis and will identify genes required in its signaling pathway for development of hearmg and balance.
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