HMGA2将相反的形态发生素信号与耳蜗长期低频听觉功能联系起来

文献信息

中文摘要

耳蜗通过沿其音调定位轴建立的分子、结构和功能特化来分辨声音频率。尽管瞬时形态发生素梯度在胚胎发生过程中建立位置信息，但随着耳蜗功能成熟，维持和细化这些信息的机制仍知之甚少。在此，我们将染色质修饰因子HMGA2确定为相反的hedgehog（HH）和视黄酸（RA）信号与长期听觉功能之间的候选分子联系。体内对RA和HH信号的操纵表明，RA抑制而HH激活促进Hmga2表达，从而建立其从顶端到基底的递减梯度。条件性敲除Hmga2不影响耳蜗长度、毛细胞数量、机械转导或Prestin定位，但导致延迟且持续的低频听力缺陷。纵向听觉测量揭示了可能导致这种缺陷的两种不同功能表型：与耳蜗微力学改变一致的非音调定位DPOAE异常，以及与内毛细胞-传入信号受损一致的晚期低频ABR P1振幅降低。总之，这些发现将HMGA2确定为胚胎形态发生素信号与长期低频听觉功能之间的分子联系，并表明持续的HMGA2依赖性调节有助于维持低频听觉功能。

英文摘要

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.