Sox3 stabilizes the actin core of hair cell stereocilia essential for hearing.

Abstract

Hearing relies on the lifelong stability of the actin core within hair cell stereocilia, yet the molecular mechanisms ensuring this stability are largely unknown. Here, we identify the transcription factor Sox3 as a key regulator of this core structure in mice. In the absence of Sox3, the stereocilia core progressively disassembles, leading to hearing loss and impaired mechanotransduction. Sox3-deficient stereocilia are also more susceptible to acoustic trauma and fail to repair structural gaps, whereas Sox3 overexpression confers resilience against noise-induced damage. Mechanistically, Sox3 deletion downregulates β-thymosin genes in hair cells, most prominently Tmsb10, an essential regulator of actin monomer availability. Depleting Tmsb10 recapitulates the core degeneration observed in Sox3-deficient hair cells, establishing the Sox3-Tmsb10 axis as a novel molecular mechanism governing the lifelong preservation of the stereocilia actin core. This regulatory pathway also represents a promising target for therapeutic intervention in noise-induced hearing loss.