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.
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.
|Singh, Sunita; Jangid, Rahul K; Crowder, Alyssa et al. (2018) Foxi3 transcription factor activity is mediated by a C-terminal transactivation domain and regulated by the Protein Phosphatase 2A (PP2A) complex. Sci Rep 8:17249|
|Gu, Rende; Brown 2nd, Rogers M; Hsu, Chih-Wei et al. (2016) Lineage tracing of Sox2-expressing progenitor cells in the mouse inner ear reveals a broad contribution to non-sensory tissues and insights into the origin of the organ of Corti. Dev Biol 414:72-84|
|Singh, Sunita; Groves, Andrew K (2016) The molecular basis of craniofacial placode development. Wiley Interdiscip Rev Dev Biol 5:363-76|
|Basch, Martin L; Brown 2nd, Rogers M; Jen, Hsin-I et al. (2016) Where hearing starts: the development of the mammalian cochlea. J Anat 228:233-54|
|Birol, Onur; Ohyama, Takahiro; Edlund, Renée K et al. (2016) The mouse Foxi3 transcription factor is necessary for the development of posterior placodes. Dev Biol 409:139-151|
|Shirokova, Vera; Biggs, Leah C; Jussila, Maria et al. (2016) Foxi3 Deficiency Compromises Hair Follicle Stem Cell Specification and Activation. Stem Cells 34:1896-908|
|Tassano, Elisa; Jagannathan, Vidhya; Drögemüller, Cord et al. (2015) Congenital aural atresia associated with agenesis of internal carotid artery in a girl with a FOXI3 deletion. Am J Med Genet A 167A:537-44|
|Edlund, Renée K; Birol, Onur; Groves, Andrew K (2015) The role of foxi family transcription factors in the development of the ear and jaw. Curr Top Dev Biol 111:461-95|
|Jussila, Maria; Aalto, Anne J; Sanz Navarro, Maria et al. (2015) Suppression of epithelial differentiation by Foxi3 is essential for molar crown patterning. Development 142:3954-63|
|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|
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