Cortada Maurizio, Levano Soledad, Hall Michael N, Bodmer Daniel
Department of Biomedicine, University of Basel, CH-4031 Basel, Switzerland.
Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
iScience. 2023 Aug 19;26(9):107687. doi: 10.1016/j.isci.2023.107687. eCollection 2023 Sep 15.
mTOR broadly controls cell growth, but little is known about the role of mTOR complex 2 (mTORC2) in the inner ear. To investigate the role of mTORC2 in sensory hair cells (HCs), we generated HC-specific knockout (HC-RicKO) mice. HC-RicKO mice exhibited early-onset, progressive, and profound hearing loss. Increased DPOAE thresholds indicated outer HC dysfunction. HCs are lost, but this occurs after hearing loss. Ultrastructural analysis revealed stunted and absent stereocilia in outer HCs. In inner HCs, the number of synapses was significantly decreased and the remaining synapses displayed a disrupted actin cytoskeleton and disorganized Ca channels. Thus, the mTORC2 signaling pathway plays an important role in regulating auditory HC structure and function via regulation of the actin cytoskeleton. These results provide molecular insights on a central regulator of cochlear HCs and thus hearing.
哺乳动物雷帕霉素靶蛋白（mTOR）广泛控制细胞生长，但对于mTOR复合物2（mTORC2）在内耳中的作用却知之甚少。为了研究mTORC2在感觉毛细胞（HCs）中的作用，我们构建了毛细胞特异性敲除（HC-RicKO）小鼠。HC-RicKO小鼠表现出早发性、进行性和严重的听力损失。畸变产物耳声发射（DPOAE）阈值升高表明外毛细胞功能障碍。毛细胞会丢失，但这发生在听力损失之后。超微结构分析显示外毛细胞中的静纤毛发育不良和缺失。在内毛细胞中，突触数量显著减少，剩余的突触显示肌动蛋白细胞骨架破坏和钙通道紊乱。因此，mTORC2信号通路通过调节肌动蛋白细胞骨架在调节听觉毛细胞结构和功能中起重要作用。这些结果为耳蜗毛细胞及听力的核心调节因子提供了分子层面的见解。
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