title: In Vivo Interplay between p27Kip1, GATA3, ATOH1, and POU4F3 Converts Non-sensory Cells to Hair Cells in Adult Mice.
abstract: Hearing loss is widespread and persistent because mature mammalian auditory hair cells (HCs) are nonregenerative. In mice, the ability to regenerate HCs from surrounding supporting cells (SCs) declines abruptly after postnatal maturation. We find that combining p27Kip1deletion with ectopic ATOH1 expression surmounts this age-related decline, leading to conversion of SCs to HCs in mature mouse cochleae and after noise damage. p27Kip1deletion, independent of canonical effects on Rb-family proteins, upregulated GATA3, a co-factor for ATOH1 that is lost from SCs with age. Co-activation of GATA3 or POU4F3 and ATOH1 promoted conversion of SCs to HCs in adult mice. Activation of POU4F3 alone also converted mature SCs to HCs in vivo. These data illuminate a genetic pathway that initiates auditory HC regeneration and suggest p27Kip1, GATA3, and POU4F3 as additional therapeutic targets for ATOH1-mediated HC regeneration.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Walters
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Coak
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dearman
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Bailey
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Kuo
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: jian.zuo@stjude.org.
authors.forename: Jian
authors.initials: J
authors.lastname: Zuo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D003051:Cochlea / Q000254:growth & development / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D050990:GATA3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006198:Hair Cells, Auditory / Q000378:metabolism / Q000473:pathology; D034381:Hearing Loss / Q000235:genetics* / Q000473:pathology; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D012038:Regeneration / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D050821:Transcription Factor Brn-3C / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D050990:GATA3 Transcription Factor; D018398:Homeodomain Proteins; D050821:Transcription Factor Brn-3C; C500943:Atoh1 protein, mouse; C493961:Cdkn1b protein, mouse; C494748:Gata3 protein, mouse; C121290:Pou4f3 protein, mouse
keywords: aging; cancer; cochlea; development; differentiation; hearing; proliferation; regeneration; sensory