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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,1,7]]},"abstract":"<jats:p>\n                    Myosin-VIIA (MYO7A) is an unconventional myosin responsible for syndromic (Usher 1B) or nonsyndromic forms of deafness in humans when mutated. In the cochlea, MYO7A is expressed in hair cells, where it is believed to act as the motor protein tensioning the mechanoelectrical transducer (MET) channels, thus setting their resting open probability (\n                    <jats:italic>\n                      P\n                      <jats:sub>o<\/jats:sub>\n                    <\/jats:italic>\n                    ). However, direct evidence for this unique role for an unconventional myosin in mature hair cells is lacking. Here, we show that MYO7A has a distinct role in hair cells, being crucial for the structural integrity of hair bundles. Postnatal deletion of\n                    <jats:italic>Myo7a<\/jats:italic>\n                    leads to 87 to 96% reduction in MYO7A from hair cells by postnatal day 20 (P20), without affecting hearing function. During the following week, mice showed progressive decline in both hearing function and MET current amplitude in hair cells without affecting the resting\n                    <jats:italic>\n                      P\n                      <jats:sub>o<\/jats:sub>\n                    <\/jats:italic>\n                    and calcium sensitivity of the MET channel. Hair-bundle stiffness was normal at P20 but halved at P30, despite it having a normal staircase morphology and tip links. The reduction of MYO7A in the stereocilia (&gt;87%) increased their vulnerability to sound-induced damage, with significantly more hearing loss and hair bundle deterioration than in control mice. RNA-sequencing identified a downregulation of several stereociliary genes in the\n                    <jats:italic>Myo7a<\/jats:italic>\n                    -deficient cochlea, indicating the presence of indirect compensatory mechanisms. This study reveals that mature hair cells seem to use a MYO7A-independent mechanism to maintain the resting\n                    <jats:italic>\n                      P\n                      <jats:sub>o<\/jats:sub>\n                    <\/jats:italic>\n                    of the MET channels. Instead, MYO7A is essential for maintaining the structural and functional integrity of the hair bundles.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2414707122","type":"journal-article","created":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T14:00:24Z","timestamp":1735826424000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":23,"title":["MYO7A is required for the functional integrity of the mechanoelectrical transduction complex in hair cells of the adult cochlea"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6876-861X","authenticated-orcid":false,"given":"Anna","family":"Underhill","sequence":"first","affiliation":[{"name":"School of Biosciences, University of Sheffield","place":["Sheffield, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Webb","sequence":"additional","affiliation":[{"name":"School of Biosciences, University of Sheffield","place":["Sheffield, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1303-6710","authenticated-orcid":false,"given":"Fiorella C.","family":"Grandi","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, Institute de Myologie, Centre de Researche en Myologie","place":["Paris, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6274-8597","authenticated-orcid":false,"given":"Jing-Yi","family":"Jeng","sequence":"additional","affiliation":[{"name":"School of Biosciences, University of Sheffield","place":["Sheffield, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6182-3527","authenticated-orcid":false,"given":"Jacques B.","family":"de Monvel","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de la Cit\u00e9 de Paris, Institut Pasteur, Assistance publique - H\u00f4pitaux de Paris, Inserm, Fondation pour l\u2019audition, CNRS, Instituts Hospitalo-Universitaires reConnect","place":["Paris, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2008-4715","authenticated-orcid":false,"given":"Baptiste","family":"Plion","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de la Cit\u00e9 de Paris, Institut Pasteur, Assistance publique - H\u00f4pitaux de Paris, Inserm, Fondation pour l\u2019audition, CNRS, Instituts Hospitalo-Universitaires reConnect","place":["Paris, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1054-3901","authenticated-orcid":false,"given":"Adam J.","family":"Carlton","sequence":"additional","affiliation":[{"name":"School of Biosciences, University of Sheffield","place":["Sheffield, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana E.","family":"Amariutei","sequence":"additional","affiliation":[{"name":"School of Biosciences, University of Sheffield","place":["Sheffield, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niovi","family":"Voulgari","sequence":"additional","affiliation":[{"name":"School of Biosciences, University of Sheffield","place":["Sheffield, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7691-5635","authenticated-orcid":false,"given":"Francesca","family":"De Faveri","sequence":"additional","affiliation":[{"name":"School of Biosciences, University of Sheffield","place":["Sheffield, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5366-341X","authenticated-orcid":false,"given":"Federico","family":"Ceriani","sequence":"additional","affiliation":[{"name":"School of Biosciences, University of Sheffield","place":["Sheffield, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8998-279X","authenticated-orcid":false,"given":"Mirna","family":"Mustapha","sequence":"additional","affiliation":[{"name":"School of Biosciences, University of Sheffield","place":["Sheffield, United Kingdom"]},{"name":"Neuroscience Institute, University of Sheffield","place":["Sheffield, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart L.","family":"Johnson","sequence":"additional","affiliation":[{"name":"School of Biosciences, University of Sheffield","place":["Sheffield, United Kingdom"]},{"name":"Neuroscience Institute, University of Sheffield","place":["Sheffield, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6159-0572","authenticated-orcid":false,"given":"Saaid","family":"Safieddine","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de la Cit\u00e9 de Paris, Institut Pasteur, Assistance publique - 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Zou , The roles of USH1 proteins and PDZ domain containing USH proteins in USH2 complex integrity in cochlear hair cells. Hum. Mol. Genet. 26, 624\u2013636 (2017).","journal-title":"Hum. Mol. Genet."},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0342-07.2007"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2005.095661"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1999.9424"},{"key":"e_1_3_4_48_2","unstructured":"A. Underhill MYO7a is required for the functional integrity of the mechanoelectrical transduction complex in the outer hair cells of the adult cochlea. GEO. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE246143. 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