In Vivo Interplay between p27Kip1, GATA3, ATOH1, and POU4F3 Converts Non-sensory Cells to Hair Cells in Adult Mice

Cell Rep. 2017 Apr 11;19(2):307-320. doi: 10.1016/j.celrep.2017.03.044.

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 p27Kip1 deletion with ectopic ATOH1 expression surmounts this age-related decline, leading to conversion of SCs to HCs in mature mouse cochleae and after noise damage. p27Kip1 deletion, 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.

Keywords: aging; cancer; cochlea; development; differentiation; hearing; proliferation; regeneration; sensory.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Cell Proliferation / genetics
  • Cochlea / growth & development
  • Cochlea / pathology
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics*
  • GATA3 Transcription Factor / biosynthesis*
  • GATA3 Transcription Factor / genetics
  • Gene Expression Regulation, Developmental
  • Hair Cells, Auditory / metabolism
  • Hair Cells, Auditory / pathology
  • Hearing Loss / genetics*
  • Hearing Loss / pathology
  • Homeodomain Proteins / biosynthesis*
  • Homeodomain Proteins / genetics
  • Humans
  • Mice
  • Regeneration / genetics
  • Signal Transduction / genetics
  • Transcription Factor Brn-3C / biosynthesis*
  • Transcription Factor Brn-3C / genetics

Substances

  • Atoh1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Cdkn1b protein, mouse
  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Homeodomain Proteins
  • Pou4f3 protein, mouse
  • Transcription Factor Brn-3C
  • Cyclin-Dependent Kinase Inhibitor p27