HMGA2 links opposing morphogen signaling to long-term low-frequency auditory function in the cochlea.

The cochlea resolves sound frequencies through molecular, structural, and functional specializations established along its tonotopic axis. Although transient morphogen gradients establish positional information during embryogenesis, the mechanisms that maintain and refine this information as cochlear function matures remain poorly understood. Here, we identify the chromatin modifier HMGA2 as a candidate molecular link between opposing hedgehog (HH) and retinoic acid (RA) signals and long-term auditory function. In vivo manipulation of RA and HH signaling demonstrated that RA suppresses, whereas HH activation promotes, Hmga2 expression, establishing its apex-to-base decreasing gradient. Conditional deletion of Hmga2 did not affect cochlear length, hair cell numbers, mechanotransduction, or Prestin localization but caused a delayed and persistent low-frequency hearing deficit. Longitudinal auditory measurements revealed two distinct functional phenotypes that may contribute to this deficit: non-tonotopic DPOAE abnormalities consistent with altered cochlear micromechanics and a late, low-frequency reduction in ABR P1 amplitude consistent with impaired inner hair cell-afferent signaling. Together, these findings identify HMGA2 as a molecular link between embryonic morphogen signaling and long-term low-frequency auditory function and suggest that persistent HMGA2-dependent regulation contributes to the maintenance of low-frequency auditory function.