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

• DOI: 10.1016/j.celrep.2017.03.044
• Publication Date: 2017-04-11T18:08:45Z
• Authors: Bradley J. Walters; Emily Coak; Jennifer Dearman; Grace Bailey; Tetsuji Yamashita; Bryan Kuo; Jian Zuo
• Keywords: Homeodomain Proteins; 0303 health sciences; QH301-705.5; Gene Expression Regulation, Developmental; GATA3 Transcription Factor; Cochlea; Transcription Factor Brn-3C; Mice; 03 medical and health sciences; Animals, Newborn; Hair Cells, Auditory; Basic Helix-Loop-Helix Transcription Factors; Animals; Humans; Regeneration; Biology (General); Hearing Loss; Cyclin-Dependent Kinase Inhibitor p27; Cell Proliferation; Signal Transduction

Highlights•Co-manipulation of ATOH1 and p27Kip1 creates new cochlear hair cells in adult mice•p27Kip1 noncanonically inhibits GATA3, an Atoh1 co-factor that promotes POU4F3•Ectopic POU4F3 upregulates cell markers supporting cochleae•ATOH1-based therapies may be improved by co-manipulation p27Kip1, or POU4F3SummaryHearing loss is widespread persistent because mature mammalian auditory (HCs) are nonregenerative. In mice, the ability to regenerate HCs from surrounding (SCs) declines abruptly after postnatal maturation. We find combining deletion with ectopic expression surmounts this age-related decline, leading conversion SCs mouse cochleae noise damage. deletion, independent canonical effects on Rb-family proteins, upregulated a for lost age. Co-activation GATA3 promoted mice. Activation alone also converted vivo. These data illuminate genetic pathway initiates HC regeneration suggest as additional therapeutic targets ATOH1-mediated regeneration.Graphical abstract