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 preliminary evidence 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 pinna begins to form in Foxi3 mutants, but rapidly succumbs to massive cell death. 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. Preliminary evidence 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 ear.

Public Health Relevance

1 in 1000 children are born with some form of inherited hearing loss. We have identified a new gene, Foxi3, that is activated very early in the development of the ear and causes a severe disruption of the inner ear, middle ear and external ear when mutated. We believe that understanding the function of this gene may help to shed light on the causes of human birth defects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
3R01DC013072-01S1
Application #
8698904
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2013-03-22
Project End
2016-02-28
Budget Start
2013-08-01
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$32,413
Indirect Cost
$11,702
Name
Baylor College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Khatri, Safia B; Edlund, Renée K; Groves, Andrew K (2014) Foxi3 is necessary for the induction of the chick otic placode in response to FGF signaling. Dev Biol 391:158-69
Groves, Andrew K; LaBonne, Carole (2014) Setting appropriate boundaries: fate, patterning and competence at the neural plate border. Dev Biol 389:2-12
Edlund, Renée K; Ohyama, Takahiro; Kantarci, Husniye et al. (2014) Foxi transcription factors promote pharyngeal arch development by regulating formation of FGF signaling centers. Dev Biol 390:1-13