title: Eya1-Six1 interaction is sufficient to induce hair cell fate in the cochlea by activating Atoh1 expression in cooperation with Sox2.
abstract: Inner-ear hair cell differentiation requires Atoh1 function, while Eya1, Six1, and Sox2 are coexpressed in sensory progenitors and mutations in these genes cause sensorineural hearing loss. However, how these genes are linked functionally and the transcriptional networks controlling hair cell induction remain unclear. Here, we show (1) that Eya1/Six1 are necessary for hair cell development, and their coexpression in mouse cochlear explants is sufficient to induce hair cell fate in the nonsensory epithelium expressing low-level Sox2 by activating not only Atoh1-dependent but also Atoh1-independent pathways and (2) that both pathways induce Pou4f3 to promote hair cell differentiation. Sox2 cooperates with Eya1/Six1 to synergistically activate Atoh1 transcription via direct binding to the conserved Sox- and Six-binding sites in Atoh1 enhancers, and these proteins physically interact. Our findings demonstrate that direct and cooperative interactions between the Sox2, Six1, and Eya1 proteins coordinate Atoh1 expression to specify hair cell fate.
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Mohi
authors.initials: M
authors.lastname: Ahmed
authors.forename: Elaine Y M
authors.initials: EY
authors.lastname: Wong
authors.forename: Jianbo
authors.initials: J
authors.lastname: Sun
authors.forename: Jinshu
authors.initials: J
authors.lastname: Xu
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Pin-Xian
authors.initials: PX
authors.lastname: Xu
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D003051:Cochlea / Q000166:cytology / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D018274:Electroporation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006198:Hair Cells, Auditory / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D017027:Protein Tyrosine Phosphatases; D055748:SOXB1 Transcription Factors; C500943:Atoh1 protein, mouse; C490947:Six1 protein, mouse; C527783:Sox2 protein, mouse; C501156:Eya1 protein, mouse