Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178, USA.
Department of Otorhinolaryngology-Head and Neck Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
J Cell Sci. 2021 Apr 1;134(7). doi: 10.1242/jcs.254458. Epub 2021 Apr 13.
Hearing loss affects ∼10% of adults worldwide. Most sensorineural hearing loss is caused by the progressive loss of mechanosensitive hair cells (HCs) in the cochlea. The molecular mechanisms underlying HC maintenance and loss remain poorly understood. LBH, a transcription co-factor implicated in development, is abundantly expressed in outer hair cells (OHCs). We used Lbh-null mice to identify its role in HCs. Surprisingly, Lbh deletion did not affect differentiation and the early development of HCs, as nascent HCs in Lbh knockout mice had normal looking stereocilia. The stereocilia bundle was mechanosensitive and OHCs exhibited the characteristic electromotility. However, Lbh-null mice displayed progressive hearing loss, with stereocilia bundle degeneration and OHC loss as early as postnatal day 12. RNA-seq analysis showed significant gene enrichment of biological processes related to transcriptional regulation, cell cycle, DNA damage/repair and autophagy in Lbh-null OHCs. In addition, Wnt and Notch pathway-related genes were found to be dysregulated in Lbh-deficient OHCs. Our study implicates, for the first time, loss of LBH function in progressive hearing loss, and demonstrates a critical requirement of LBH in promoting HC survival in adult mice.
听力损失影响全球约 10%的成年人。大多数感音神经性听力损失是由于耳蜗中机械敏感的毛细胞（HCs）渐进性丧失引起的。维持和丧失 HC 的分子机制仍知之甚少。LBH 是一种与发育有关的转录共因子，在外毛细胞（OHCs）中大量表达。我们使用 Lbh 基因敲除小鼠来确定其在 HCs 中的作用。令人惊讶的是，Lbh 缺失并不影响 HCs 的分化和早期发育，因为 Lbh 基因敲除小鼠中的新生 HCs 具有正常的静纤毛。纤毛束具有机械敏感性，OHCs 表现出特征性的电运动。然而，Lbh 基因敲除小鼠表现出进行性听力损失，早在出生后 12 天就出现纤毛束退化和 OHC 丧失。RNA-seq 分析显示，Lbh 基因敲除 OHCs 中与转录调控、细胞周期、DNA 损伤/修复和自噬相关的生物学过程的基因显著富集。此外，还发现 Wnt 和 Notch 通路相关基因在 Lbh 缺陷型 OHCs 中失调。我们的研究首次表明 LBH 功能丧失与进行性听力损失有关，并证明了 LBH 在促进成年小鼠 HC 存活中的关键作用。
