Notch Signaling in Ear Development

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DESCRIPTION (provided by applicant): The mammalian inner ear is an exquisitely complex organ composed of a fluid-filled duct system punctuated by highly patterned sensory regions necessary for hearing and balance. Unfortunately, when damaged, the mammalian ear demonstrates little or no ability to regenerate these regions, making understanding their development an important prerequisite for the design of future therapies. This proposal seeks to test the role of one putative sensory gene, the Notch ligand Jagged 1 (Jag1). Notch signaling has previously been demonstrated to be important for hair cell and supporting cell differentiation by mediating lateral inhibition. However, it is clear from previous studies that Jag1 is unlikely to play a major role in lateral inhibition. This proposal will test the hypothesis that Jag1 is instead involved in sensory organ specification in the ear. A major impediment to understanding the role of Jag1 in ear development is that mice deleted for this gene die early during embryogenesis. In order to circumvent this problem, a conditional loss-of-function allele will be created using the Cre/loxP system. Preliminary data shows that there are modifier(s) in the C3H inbred mouse strain that cause ear defects in Jag1 + mice. Identifying genes that interact with Jag1 will further elucidate the role that this Notch ligand plays in ear development and potentially identify new genes involved in sensory specification in the ear. We propose to map and eventually clone these modifier(s). Data collected from these experiments will further our understanding of sensory field specification in the mammalian inner ear, providing a basis for eventually correcting environmental or genetic insults to these regions.