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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.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa045","type":"journal-article","created":{"date-parts":[[2020,3,10]],"date-time":"2020-03-10T12:29:11Z","timestamp":1583843351000},"page":"2004-2021","source":"Crossref","is-referenced-by-count":17,"title":["Tmc proteins are essential for zebrafish hearing where Tmc1 is not obligatory"],"prefix":"10.1093","volume":"29","author":[{"given":"Zongwei","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"},{"name":"Department of Biology, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaoyuan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"},{"name":"Department of Biology, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kayla","family":"Kindig","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"},{"name":"Department of Biology, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengxuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"},{"name":"Department of Biology, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shih-Wei","family":"Chou","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"},{"name":"Department of Biology, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robin Woods","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"},{"name":"Department of Biology, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael R","family":"Dercoli","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"},{"name":"Department of Biology, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah","family":"Weaver","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"},{"name":"Department of Biology, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruben","family":"Stepanyan","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"},{"name":"Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr","given":"Brian M","family":"McDermott","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"},{"name":"Department of Biology, Case Western Reserve University, Cleveland, OH 44106, USA"},{"name":"Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"},{"name":"Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,3,13]]},"reference":[{"key":"2020073002371417600_ref1","volume-title":"Elementos de t\u00e9cnica microgr\u00e1fica del sistema nervioso","author":"Ramon y Cajal","year":"1933"},{"key":"2020073002371417600_ref2","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1098\/rspl.1894.0063","article-title":"Croonian lecture: la fine structure des centres nerveux","volume":"55","author":"Ram\u00f3n y Cajal","year":"1894","journal-title":"Proc. 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