title: Selection of cell fate in the organ of Corti involves the integration of Hes/Hey signaling at the Atoh1 promoter.
abstract: Determination of cell fate within the prosensory domain of the developing cochlear duct relies on the temporal and spatial regulation of the bHLH transcription factor Atoh1. Auditory hair cells and supporting cells arise in a wave of differentiation that patterns them into discrete rows mediated by Notch-dependent lateral inhibition. However, the mechanism responsible for selecting sensory cells from within the prosensory competence domain remains poorly understood. We show in mice that rather than being upregulated in rows of cells, Atoh1 is subject to transcriptional activation in groups of prosensory cells, and that highly conserved sites for Hes/Hey repressor binding in the Atoh1 promoter are needed to select the hair cell and supporting cell fate. During perinatal supporting cell transdifferentiation, which is a model of hair cell regeneration, we show that derepression is sufficient to induce Atoh1 expression, suggesting a mechanism for priming the 3' Atoh1 autoregulatory enhancer needed for hair cell expression.
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Biology at USC, 1425 San Pablo St., Los Angeles, CA 90033, USA GMCB Graduate Program, Keck School of Medicine of the University of Southern California, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Biology at USC, 1425 San Pablo St., Los Angeles, CA 90033, USA.
authors.forename: Yassan
authors.initials: Y
authors.lastname: Abdolazimi
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Biology at USC, 1425 San Pablo St., Los Angeles, CA 90033, USA.
authors.forename: Zlatka
authors.initials: Z
authors.lastname: Stojanova
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Biology at USC, 1425 San Pablo St., Los Angeles, CA 90033, USA Caruso Department of Otolaryngology - Head and Neck Surgery, Keck School of Medicine of the University of Southern California, 1450 San Pablo St., Suite 5100, Los Angeles, CA 90033, USA nsegil@med.usc.edu.
authors.forename: Neil
authors.initials: N
authors.lastname: Segil
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000502:physiology*; D002454:Cell Differentiation; D019070:Cell Lineage; D054338:Cell Transdifferentiation; D003051:Cochlea / Q000196:embryology* / Q000502:physiology; D004742:Enhancer Elements, Genetic; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006198:Hair Cells, Auditory / Q000502:physiology*; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009925:Organ of Corti / Q000196:embryology / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; C500943:Atoh1 protein, mouse; C489734:Hes1 protein, mouse; C489685:Hes5 protein, mouse; C120420:Hey1 protein, mouse
keywords: Atoh1; Cochlear development; Hair cell regeneration; Hes5; Mouse; Organ of Corti; Transdifferentiation