The major goal of this proposal is to determine the regulatory hierarchy by which Eya1, a key gene required for otic induction, controls ear morphogenesis. Recently, it was found that haploinsufficiency for human EYA1 results in Branchio-Oto-Renal (BOR) syndrome, a congenital birth defects that accounts for as many as 2% of profoundly deaf children. EYA1 is the human homologue of the Drosophila eyes absent gene, a regulatory gene for early fly eye development. The Eya gene products contains a divergent N-terminal transactivation domain and highly conserved 271 amino acid C-terminal Eya domain that participates in protein-protein interactions with Sine oculis (So) and Dachshund (Dac), which are encoded by two regulatory genes involved in early fly eye development. Genetic studies by the applicant and the others have prove that the Eya genes function downstream of Pas6 both in mice and flies. Besides the developing eye, Eya genes are widely co-expressed with Pas and Si (murine homologs in Drosophila so) genes in mammalian development, suggesting possible molecular interactions between their gene products. During ear development, Eya1 is expressed in the otic placode and periotic mesenchyme, however the steps at with Eya1 functions in early otic induction and the basis of organ defects in BOR syndrome are unclear. Moreover, although a large number of otic genes have even recently isolated, the molecular and genetic pathways regulating auditory system development is not established. I have used gene targeting in mice to generate Eya1 mutant mice. In Eya1-/- embryos, the inner ear development arrests at the otic vesicle stage, indicating that Eya1 is a key gene required for early otic morphogenesis. Molecularly, Six1 but not Pax2 and Pax8 expression in the otic vesicle depends upon Eya1 function, suggesting that a conserved Pax-Eya-Six regulatory hierarchy us utilized in otic morphogenesis. To determine a genetic pathway controlling early otic morphogenesis, I will: 1) continue the functional analysis of the Eya domain region of Eya1 protein, (2) test the elements responsible for Eya1 otic placodal expression. These studies should provide important clues as to the precise identities of other components of the genetic pathways that regulate otic morphogenesis.
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