Characterization of the Key Mouse Cochlear Developmental Genes for Auditory Hair Cell Regeneration

Mammalian inner ear cochlear auditory hair cells (HCs) and adjacent supporting cells (SCs) are believed to derive from the same progenitors during development. However, unlike SCs of nonmammalian vertebrates, mammalian cochlear SCs cannot be converted into functional hair cells (HCs) after damage, thus leading to permanent deafness. To entitle mammals with the ability to restore hearing capacity after HC damage, we first achieved proliferation of SCs by acute ablation of p27 or Sox2. Secondly, we overactivated Notch1 signaling in the mouse inner ear at different developmental stages, and found that the ability of Notch signaling in generating new HCs declines after birth. Last, we achieved reprogramming of neonatal and juvenile, but not adult, SCs into HCs, through ectopically expressing Atoh1 in SCs. Taken together, Atoh1 is able to reprogram SCs into HCs, and inactivation of p27 or Sox2 can achieve proliferation of SCs. This work builds the foundation for future HC regeneration studies. Combining these two manipulations may represent a promising approach to recapitulate the cellular events occurring in the process of HC regeneration in non-mammalian vertebrates