Tox regulates hair cell stereocilia development and Cdh23 expression in mice and zebrafish.

Abstract

Auditory hair cells (HCs) are critical sensory units for sound detection, and their development requires precise transcriptional regulation. To date, numerous transcription factors crucial for HC development have been characterized; however, the governing regulatory network remains unclear and warrants further investigation. In this study, we identified the transcription factor <i>Tox</i>, which plays a significant role in HC development. <i>Tox</i> is highly expressed in HCs in both zebrafish and mice, and its expression increases along developmental pseudotime, rising after <i>Atoh1</i> and preceding <i>Myo7a</i>, suggesting a potential role in development. Utilizing <i>Tox</i> mutant models in zebrafish and mice, we found that <i>Tox</i> is essential for HC functional maintenance and stereocilia stability. Through multiomics integrated analysis, we confirmed that <i>Tox</i> directly binds to conserved motifs in the <i>Cdh23</i> promoter, drives its transcription, and ensures the precise localization of Cdh23 at the tips of stereocilia, thereby playing a key role in maintaining auditory function. In conclusion, our findings indicate that <i>Tox</i> influences HC development by regulating the transcription and translation of <i>Cdh23</i>, enriches the regulatory network of HC development, and may serve as a target for clinical gene therapy for deafness.