A regulatory axis for tonotopic MYO7A expression in cochlear hair cells.

Abstract

<i>Myo7a</i>, a gene mutated in Usher syndrome and nonsyndromic deafness, encodes an unconventional myosin essential for hair cell function. Our previous work revealed that cochlear hair cells express distinct <i>Myo7a</i> isoforms with unique spatial and cell type-specific patterns. The canonical isoform (<i>Myo7a-C</i>) and an additional isoform (<i>Myo7a-N</i>) are co-expressed in outer hair cells (OHCs) but exhibit opposing tonotopic gradients, while inner hair cells primarily express <i>Myo7a-C</i>. These isoforms arise from distinct transcriptional start sites, indicating separate regulatory inputs. Here, we identify an intronic <i>cis-</i>regulatory element, <i>EnhancerA</i>, essential for tonotopically graded <i>Myo7a</i> expression. <i>EnhancerA</i> deletion reduces MYO7A protein levels in a tonotopically varied manner, 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 <i>EnhancerA</i> to regulate <i>Myo7a-N</i> in OHCs. These findings define a <i>cis-trans</i> regulatory axis critical for isoform-specific <i>Myo7a</i> expression and cochlear function.