Endogenous Sox2 expression is essential for Atoh1-induced hair cell addition and regeneration in the mouse utricle

The limited regenerative capacity of vestibular hair cells (HCs) in mammals is one of the causes of permanent balance disorders. The transcription factor Atoh1 has been identified as a potential candidate for inducing HC regeneration. However, regulation of Atoh1 alone has proven insufficient to achieve functional recovery of the mammalian vestibule. Elucidating the mechanisms underlying Atoh1-induced regeneration may therefore inform strategies to enhance its therapeutic efficacy. Endogenous Sox2 is required for Atoh1-associated HC formation during embryonic development, yet its role in Atoh1 overexpression-induced HC formation after birth remains unclear. In this study, we conditionally knocked down Sox2 while overexpressing Atoh1 in the utricle of neonatal mice or in diphtheria-toxin-injured adult mice. Atoh1 overexpression stimulated supporting cell proliferation and new HC formation in neonates; however, concomitant Sox2 knockdown attenuated the effects. In the diphtheria-toxin-injured adult utricle, Sox2 downregulation similarly weakened Atoh1-induced HC regeneration. These findings demonstrate that endogenous Sox2 expression is essential for Atoh1-induced HC addition and regeneration in the mouse utricle.