Deciphering the genetic interactions between Pou4f3, Gfi1, and Rbm24 in maintaining mouse cochlear hair cell survival.

Abstract

Mammals harbor a limited number of sound-receptor hair cells (HCs) that cannot be regenerated after damage. Thus, investigating the underlying molecular mechanisms that maintain HC survival is crucial for preventing hearing impairment. Intriguingly, <i>Pou4f3^-/-</i> or <i>Gfi1^-/-</i> HCs form initially but then rapidly degenerate, whereas <i>Rbm24^-/-</i> HCs degenerate considerably later. However, the transcriptional cascades involving Pou4f3, Gfi1, and Rbm24 remain undescribed. Here, we demonstrate that <i>Rbm24</i> expression is completely repressed in <i>Pou4f3^-/-</i> HCs but unaltered in <i>Gfi1^-/-</i> HCs, and further that the expression of both POU4F3 and GFI1 is intact in <i>Rbm24^-/-</i> HCs. Moreover, by using in vivo mouse transgenic reporter assays, we identify three <i>Rbm24</i> enhancers to which POU4F3 binds. Lastly, through in vivo genetic testing of whether Rbm24 restoration alleviates the degeneration of <i>Pou4f3^-/-</i> HCs, we show that ectopic Rbm24 alone cannot prevent <i>Pou4f3^-/-</i> HCs from degenerating. Collectively, our findings provide new molecular and genetic insights into how HC survival is regulated.