Nakano, Y.; Driver, E. C.; Wiechert, S. C.; Peguero, B.; Boger, E. T.; Allamargot, C.; Hipp, R.; Doetzlhofer, A.; Morell, R. J.; Kelley, M. W.; Banfi, B.

The transcriptional activator ATOH1 is a master regulator of the development of mechanosensory hair-cells (HCs) in the ear. We report that the ATOH1 target gene Casz1 encodes a transcription factor that regulates the rate of outer HC (OHC) maturation by gene repression. Genetic deletion of Casz1 during (but not after) development of the mouse cochlea caused: hearing loss; abnormal organization of mechanosensory stereocilia bundles in OHCs; abnormally low F-actin density in OHC cuticular plates; progressive loss of OHCs; and mild morphological alterations in inner HCs. RNA sequencing revealed that Casz1 deletion delayed downregulation of genes expressed in immature OHCs, including the actin regulator-encoding gene Coro2a, and accelerated upregulation of genes expressed in mature OHCs. Coro2a knockdown restored the density of cuticular plate F-actin in Casz1 mutant OHCs. Our data indicate that CASZ1 regulates transcriptional and morphological maturation of OHCs, and that CASZ1 in maturing HCs is necessary for hearing.