Receptor tyrosine kinases are known to play a key role in the development of non-neuronal cells in neural tissue. Recent data from investigations of FGF receptors in the developing cochlea have shown that a specific FGF receptor FGFR3 is required for the differentiation of a group of glial-like support cells of the inner ear's sensory epithelium, the pillar cells. This system provides the unique advantage of having a highly stereotyped population of glial-like cells that can be readily identified. The experiments outlined in this proposal will lead to further understanding of the molecular mechanisms that control the differentiation of this important type of support cell, with the following specific aims. 1. To determine the time in development when Fgfr3 is first required for Pillar cells. 2. To examine pillar cell development in mice with constitutively activated mutations. 3. To examine the expression of candidate FGFR3 ligands in the developing cochlea. 4. To examine the effect on Pillar cell differentiation of elimination of FGF8 from the inner hair cells at different stages of development. 5. To determine whether FGF8 can promote pillar cell differentiation. The studies we have proposed will extend our understanding of the role of FGF-FGFR signaling in the development and maintenance of the differentiated phenotypes in the cochlea; our long term aims are to use this information to better understand congenital defects in this system and to ultimately promote its repair.
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