Tremendous progress has been made during the last five years in the mapping and cloning of genes responsible for syndromic and nonsyndromic hereditary hearing loss. The mouse is an excellent animal model for the study of these human conditions because the anatomy, function and hereditary abnormalities of the ear have been shown to be similar in both humans and mice. We have recently described one such model resulting from a spontaneous mutation in a C3HIHeJ colony of mice at the Jackson Laboratory. The insertion of a retrotransposon (intracisternal A particle) into an intron of Eyal was associated with reduced expression of the normal Eya] message and inner ear and kidney abnormalities. We have designated this mutation Eya1 bor The human homologue of this gene, EYAJ, has been shown to underlie Branchio-Oto-Renal (B OR) syndrome, an autosomal dominant disorder characterized by hearing loss with associated branchial and renal anomalies. The function of this new class of nuclear protein is poorly understood. Our preliminary data, and that of our collaborators, suggests a critical role for this gene, and other members of this gene family (Eyal-4), in inner ear morphogenesis and postnatal function. In this proposal we intend to explore the hypothesis that Eyal participates in a regulatory network, as Jescribed in the Drosophila eye (eya), that is conserved and critical, in a dose dependent manner, to the early inductive events in mammalian ear development and maintenance of the mature auditory phenotype. We will examine the dose dependent effects on the ear and related structures, in viva, anatomically, functionally and molecularly. This will be accomplished by studying the Fl mice resulting from a cross between C3H/HeJ Eyalb0r/+ and BALB/cJ Eya1+/- and Eyal over-expression transgenic mutants. Additionally, we will identify the regions of the Eya homologous region (EyaHR) that are critical to the protein-protein interactions with other members of this conserved transcriptional regulatory complex. These and future experiments represent the natural progression from my Mentored Clinical Scientist Development Award (K08).
