Mammalian Genetics Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kami-kitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
Laboratory of Animal Resources and Development, Tokyo University of Agriculture, 196 Yasaka, Abashiri, Hokkaido, 099-2493, Japan.
Sci Rep. 2019 Mar 27;9(1):5285. doi: 10.1038/s41598-019-41711-2.
Outer hair cells (OHCs) are responsible for the amplification of sound, and the death of these cells leads to hearing loss. Although the mechanisms for sound amplification and OHC death have been well investigated, the effects on the cochlea after OHC death are poorly understood. To study the consequences of OHC death, we established an OHC knockout system using a novel mouse model, Prestin-hDTR, which uses the prestin promoter to express the human diphtheria toxin (DT) receptor gene (hDTR). Administration of DT to adult Prestin-hDTR mice results in the depletion of almost all OHCs without significant damage to other cochlear and vestibular cells, suggesting that this system is an effective tool for the analysis of how other cells in the cochlea and vestibula are affected after OHC death. To evaluate the changes in the cochlea after OHC death, we performed differential gene expression analysis between the untreated and DT-treated groups of wild-type and Prestin-hDTR mice. This analysis revealed that genes associated with inflammatory/immune responses were significantly upregulated. Moreover, we found that several genes linked to hearing loss were strongly downregulated by OHC death. Together, these results suggest that this OHC knockout system is a useful tool to identify biomarkers associated with OHC death.
外毛细胞（OHC）负责声音的放大，这些细胞的死亡会导致听力损失。尽管声音放大和 OHC 死亡的机制已经得到了很好的研究，但 OHC 死亡对耳蜗的影响还知之甚少。为了研究 OHC 死亡的后果，我们使用一种新型的小鼠模型 Prestin-hDTR 建立了 OHC 敲除系统，该系统利用 prestin 启动子表达人白喉毒素（DT）受体基因（hDTR）。在成年 Prestin-hDTR 小鼠中给予 DT 会导致几乎所有 OHC 耗竭，而对其他耳蜗和前庭细胞没有明显损伤，这表明该系统是分析 OHC 死亡后耳蜗和前庭中其他细胞受到影响的有效工具。为了评估 OHC 死亡后耳蜗的变化，我们对未处理和 DT 处理的野生型和 Prestin-hDTR 小鼠进行了差异基因表达分析。该分析表明，与炎症/免疫反应相关的基因显著上调。此外，我们发现几个与听力损失相关的基因因 OHC 死亡而被强烈下调。总之，这些结果表明，这种 OHC 敲除系统是一种识别与 OHC 死亡相关的生物标志物的有用工具。
