Genetic Regulation of Inner, Middle and Outer Ear Development

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PROJECT SUMMARY The mammalian inner, middle and outer ears have different embryonic origins, yet the development of each component of the auditory apparatus must be precisely synchronized in space and time. Understanding the mechanisms that regulate and co-ordinate the development of these structures is of central importance in understanding the basis of the many birth defects that affect hearing. We have identified a Forkhead transcription factor, Foxi3, that is expressed at very early stages in the embryonic head. Foxi3 mouse mutants made in our lab lack all components of the inner, middle and external ears. Our work suggests that one of the first steps in ear induction– the formation of the otic placode – does not occur in Foxi3 mutants. Moreover, the mesenchyme of the first and second branchial arches that generate the middle ear ossicles and the external ear begins to form in Foxi3 mutants, but rapidly succumbs to massive cell death. Moreover, we have recently identified human patients with Foxi3 variants that have a variety of defects in their hearing apparatus To our knowledge, Foxi3 is the only mammalian gene that causes a complete developmental failure of the entire inner, middle and outer ears when mutated by itself. We are therefore extremely interested to understand how Foxi3 orchestrates development of the auditory apparatus at both the cellular and molecular levels. Our data suggests that Foxi3 may act as a “pioneer” transcription factor – its main function in addition to initiating transcription is to epigenetically organize genomic loci containing ear-specific genes in a transcriptionally competent state. Our first two aims will determine the function and mechanism of Foxi3 during development of the inner ear using knockout mice, chick embryo manipulations and state-of-the-art ES cell models, deep sequencing and bioinformatic analysis. Our final aim focuses on the function the Foxi3 gene in the development of the middle and external ear – here we will both study the effects of loss of Foxi3 in mice, but also create mouse mutants that recapitulate the genetic variants seen in some of our human patients.