Walters Bradley J, Coak Emily, Dearman Jennifer, Bailey Grace, Yamashita Tetsuji, Kuo Bryan, Zuo Jian
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Cell Rep. 2017 Apr 11;19(2):307-320. doi: 10.1016/j.celrep.2017.03.044.
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 p27 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. p27 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 p27, GATA3, and POU4F3 as additional therapeutic targets for ATOH1-mediated HC regeneration.
听力损失普遍且持续存在，因为成熟的哺乳动物听觉毛细胞（HCs）不可再生。在小鼠中，出生后成熟后，从周围支持细胞（SCs）再生HCs的能力会突然下降。我们发现，将p27缺失与异位ATOH1表达相结合可克服这种与年龄相关的下降，导致成熟小鼠耳蜗中以及噪声损伤后SCs转化为HCs。p27缺失独立于对Rb家族蛋白的典型作用，上调了GATA3，GATA3是ATOH1的辅助因子，随着年龄的增长会从SCs中丢失。GATA3或POU4F3与ATOH1的共同激活促进了成年小鼠SCs向HCs的转化。单独激活POU4F3也可在体内将成熟的SCs转化为HCs。这些数据揭示了一条启动听觉HC再生的遗传途径，并表明p27、GATA3和POU4F3是ATOH1介导的HC再生的额外治疗靶点。
