A Regulatory Axis for Tonotopic MYO7A Expression in Cochlear Hair Cells

Myo7a , a gene mutated in Usher syndrome and non-syndromic deafness, encodes an unconventional myosin essential for hair cell function. Our previous work revealed that cochlear hair cells express distinct Myo7a isoforms with unique spatial and cell type-specific patterns. The canonical isoform ( Myo7a-C ) and a novel isoform ( Myo7a-N ) are co-expressed in outer hair cells (OHCs) but exhibit opposing tonotopic gradients, while inner hair cells (IHCs) primarily express Myo7a-C . These isoforms arise from distinct transcriptional start sites, indicating separate regulatory inputs. Here, we identify an intronic cis-regulatory element, EnhancerA , essential for tonotopically graded Myo7a expression . EnhancerA deletion reduces MYO7A protein levels, disrupts hair bundle morphogenesis, alters OHC mechanotransduction, and leads to hair cell degeneration and hearing loss. We further identify SIX2, a tonotopically expressed transcription factor that may interact with EnhancerA to regulate Myo7a-N in OHCs. These findings define a cis-trans regulatory axis critical for isoform-specific Myo7a expression and cochlear function.