Bottom Riley T, Xu Yijun, Siebald Caroline, Jung Jinsei, Müller Ulrich
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
Nat Commun. 2024 Dec 30;15(1):10899. doi: 10.1038/s41467-024-55275-x.
Deafness is the most common form of sensory impairment in humans and frequently caused by defects in hair cells of the inner ear. Here we demonstrate that in male mice which model recessive non-syndromic deafness (DFNB6), inactivation of Tmie in hair cells disrupts gene expression in the neurons that innervate them. This includes genes regulating axonal pathfinding and synaptogenesis, two processes that are disrupted in the inner ear of the mutant mice. Similar defects are observed in mouse models for deafness caused by mutations in other genes with primary functions in hair cells. Gene therapy targeting hair cells restores hearing and inner ear circuitry in DFNB6 model mice. We conclude that hair cell function is crucial for the establishment of peripheral auditory circuitry. Treatment modalities for deafness thus need to consider restoration of the function of both hair cells and neurons, even when the primary defect occurs in hair cells.
耳聋是人类最常见的感觉障碍形式，通常由内耳毛细胞缺陷引起。在此我们证明，在模拟隐性非综合征性耳聋（DFNB6）的雄性小鼠中，毛细胞中Tmie的失活会破坏支配它们的神经元中的基因表达。这包括调节轴突导向和突触发生的基因，这两个过程在突变小鼠的内耳中受到破坏。在由毛细胞中具有主要功能的其他基因突变引起的耳聋小鼠模型中也观察到类似缺陷。针对毛细胞的基因治疗可恢复DFNB6模型小鼠的听力和内耳神经回路。我们得出结论，毛细胞功能对于外周听觉神经回路的建立至关重要。因此，即使原发性缺陷发生在毛细胞中，耳聋的治疗方式也需要考虑恢复毛细胞和神经元的功能。
