Eya1-Six1 Interaction Is Sufficient to Induce Hair Cell Fate in the Cochlea by Activating Atoh1 Expression in Cooperation with Sox2
Copyright policy )Eya1-Six1 Interaction Is Sufficient to Induce Hair Cell Fate in the Cochlea by Activating Atoh1 Expression in Cooperation with Sox2
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.
- King's College London United Kingdom
- University of Hong Kong (香港大學) China (People's Republic of)
- Icahn School of Medicine at Mount Sinai United States
- Kings College London, University of London United Kingdom
- University of Hong Kong China (People's Republic of)
Homeodomain Proteins - Genetics - Metabolism, Embryo, Mammalian - Cytology - Metabolism, Basic Helix-Loop-Helix Transcription Factors - Genetics - Metabolism, Electrophoretic Mobility Shift Assay, Immunoenzyme Techniques, Mice, Basic Helix-Loop-Helix Transcription Factors, Developmental, Mutation - Genetics, Protein Tyrosine Phosphatases - Genetics - Metabolism, Phosphorylation, Auditory, Blotting, Intracellular Signaling Peptides and Proteins, Gene Expression Regulation, Developmental, Nuclear Proteins, Cell Differentiation, Intracellular Signaling Peptides And Proteins - Genetics - Metabolism, Cochlea, Mammalian - Cytology - Metabolism, Hair Cells, Soxb1 Transcription Factors - Genetics - Metabolism, Electroporation, Embryo, Western, 570, Chromatin Immunoprecipitation, Blotting, Western, Hair Cells, Auditory - Metabolism, 610, Research Support, N.I.H., Hair Cells, Auditory, Journal Article, Animals, Immunoprecipitation, Homeodomain Proteins, Mammalian, SOXB1 Transcription Factors, Extramural, Embryo, Mammalian, Cochlea - Cytology - Metabolism, Gene Expression Regulation, Mutation, Auditory - Metabolism, Protein Tyrosine Phosphatases, Nuclear Proteins - Genetics - Metabolism, Developmental Biology
Homeodomain Proteins - Genetics - Metabolism, Embryo, Mammalian - Cytology - Metabolism, Basic Helix-Loop-Helix Transcription Factors - Genetics - Metabolism, Electrophoretic Mobility Shift Assay, Immunoenzyme Techniques, Mice, Basic Helix-Loop-Helix Transcription Factors, Developmental, Mutation - Genetics, Protein Tyrosine Phosphatases - Genetics - Metabolism, Phosphorylation, Auditory, Blotting, Intracellular Signaling Peptides and Proteins, Gene Expression Regulation, Developmental, Nuclear Proteins, Cell Differentiation, Intracellular Signaling Peptides And Proteins - Genetics - Metabolism, Cochlea, Mammalian - Cytology - Metabolism, Hair Cells, Soxb1 Transcription Factors - Genetics - Metabolism, Electroporation, Embryo, Western, 570, Chromatin Immunoprecipitation, Blotting, Western, Hair Cells, Auditory - Metabolism, 610, Research Support, N.I.H., Hair Cells, Auditory, Journal Article, Animals, Immunoprecipitation, Homeodomain Proteins, Mammalian, SOXB1 Transcription Factors, Extramural, Embryo, Mammalian, Cochlea - Cytology - Metabolism, Gene Expression Regulation, Mutation, Auditory - Metabolism, Protein Tyrosine Phosphatases, Nuclear Proteins - Genetics - Metabolism, Developmental Biology
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