Department of Otolaryngology-Head and Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Department of Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
Hum Mol Genet. 2020 Jul 29;29(12):2004-2021. doi: 10.1093/hmg/ddaa045.
Perception of sound is initiated by mechanically gated ion channels at the tips of stereocilia. Mature mammalian auditory hair cells require transmembrane channel-like 1 (TMC1) for mechanotransduction, and mutations of the cognate genetic sequences result in dominant or recessive heritable deafness forms in humans and mice. In contrast, zebrafish lateral line hair cells, which detect water motion, require Tmc2a and Tmc2b. Here, we use standard and multiplex genome editing in conjunction with functional and behavioral assays to determine the reliance of zebrafish hearing and vestibular organs on Tmc proteins. Surprisingly, our approach using multiple mutant alleles demonstrates that hearing in zebrafish is not dependent on Tmc1, nor is it fully dependent on Tmc2a and Tmc2b. Hearing however is absent in triple-mutant zebrafish that lack Tmc1, Tmc2a and Tmc2b. These outcomes reveal a striking resemblance of Tmc protein reliance in the vestibular sensory epithelia of mammals to the maculae of zebrafish. Moreover, our findings disclose a logic of Tmc use where hearing depends on a complement of Tmc proteins beyond those employed to sense water motion.
听觉的感知是由位于静纤毛顶端的机械门控离子通道引发的。成熟的哺乳动物听觉毛细胞需要跨膜通道样 1（TMC1）进行机械转导，其同源遗传序列的突变会导致人类和小鼠显性或隐性遗传性耳聋形式。相比之下，检测水动的斑马鱼侧线毛细胞需要 Tmc2a 和 Tmc2b。在这里，我们使用标准和多重基因组编辑以及功能和行为分析来确定斑马鱼听觉和前庭器官对 Tmc 蛋白的依赖。令人惊讶的是，我们使用多种突变等位基因的方法表明，斑马鱼的听觉不依赖于 Tmc1，也不完全依赖于 Tmc2a 和 Tmc2b。然而，在缺乏 Tmc1、Tmc2a 和 Tmc2b 的三突变斑马鱼中，听觉是缺失的。这些结果揭示了哺乳动物前庭感觉上皮中 Tmc 蛋白依赖性与斑马鱼斑之间惊人的相似性。此外，我们的研究结果揭示了 Tmc 利用的逻辑，即听觉依赖于一组 Tmc 蛋白，而不仅仅是那些用于感知水动的蛋白。
