{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:11:17Z","timestamp":1792174277261,"version":"4.4.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,9]],"date-time":"2021-08-09T00:00:00Z","timestamp":1628467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DC015111"],"award-info":[{"award-number":["R01DC015111"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21DC005846"],"award-info":[{"award-number":["R21DC005846"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81530030"],"award-info":[{"award-number":["81530030"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81873697"],"award-info":[{"award-number":["81873697"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81500797"],"award-info":[{"award-number":["81500797"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81700902"],"award-info":[{"award-number":["81700902"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Inhibitors of differentiation\/DNA binding (Id) proteins are crucial for inner ear development, but whether Id mutations affect middle ear function remains unknown. In this study, we obtained Id1<jats:sup>\u2212\/\u2212<\/jats:sup>; Id3<jats:sup>+\/\u2212<\/jats:sup> mice and Id1<jats:sup>+\/\u2212<\/jats:sup>; Id3<jats:sup>\u2212\/\u2212<\/jats:sup> mice and carefully examined their middle ear morphology and auditory function. Our study revealed a high incidence (&amp;gt;50%) of middle ear infection in the compound mutant mice. These mutant mice demonstrated hearing impairment starting around 30 days of age, as the mutant mice presented elevated auditory brainstem response (ABR) thresholds compared to those of the littermate controls. The distortion product of otoacoustic emission (DPOAE) was also used to evaluate the conductive function of the middle ear, and we found much lower DPOAE amplitudes in the mutant mice, suggesting sound transduction in the mutant middle ear is compromised. This is the first study of the middle ears of Id compound mutant mice, and high incidence of middle ear infection determined by otoscopy and histological analysis of middle ear suggests that Id1\/Id3 compound mutant mice are a novel model for human otitis media (OM).<\/jats:p>","DOI":"10.3389\/fgene.2021.508750","type":"journal-article","created":{"date-parts":[[2021,8,9]],"date-time":"2021-08-09T07:25:20Z","timestamp":1628493920000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Hearing Loss in Id1\u2212\/\u2212; Id3+\/\u2212 and Id1+\/\u2212; Id3\u2212\/\u2212 Mice Is Associated With a High Incidence of Middle Ear Infection (Otitis Media)"],"prefix":"10.3389","volume":"12","author":[{"given":"Qingyin","family":"Zheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tihua","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aizhen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoqiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/0092-8674(90)90214-Y","article-title":"The protein Id: a negative regulator of helix-loop-helix DNA binding proteins","volume":"61","author":"Benezra","year":"1990","journal-title":"Cell"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e1002336","DOI":"10.1371\/journal.pgen.1002336","article-title":"HIF-VEGF pathways are critical for chronic otitis media in Junbo and Jeff mouse mutants","volume":"7","author":"Cheeseman","year":"2011","journal-title":"PLoS Genet."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1815","DOI":"10.1073\/pnas.88.5.1815","article-title":"An Id-related helix-loop-helix protein encoded by a growth factor-inducible gene","volume":"88","author":"Christy","year":"1991","journal-title":"Proc. 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Biol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"6840","DOI":"10.1038\/ncomms7840","article-title":"Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation","volume":"6","author":"Papaspyridonos","year":"2015","journal-title":"Nat. Commun."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.otorri.2016.02.012","article-title":"Indications and radiological findings of acute otitis media and its complications","volume":"68","author":"Pont","year":"2017","journal-title":"Acta Otorrinolaringol. 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Genet."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"e0168159","DOI":"10.1371\/journal.pone.0168159","article-title":"Ectopic mineralization and conductive hearing loss in Enpp1asj mutant mice, a new model for otitis media and tympanosclerosis","volume":"11","author":"Tian","year":"2016","journal-title":"PLoS One"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1023\/B:APPT.0000025804.25396.79","article-title":"Id-1 expression and cell survival","volume":"9","author":"Wong","year":"2004","journal-title":"Apoptosis"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"14913","DOI":"10.1038\/s41598-018-33337-7","article-title":"Hyaluronic acid-CD44 interactions promote BMP4\/7-dependent Id1\/3 expression in melanoma cells","volume":"8","author":"Wu","year":"2018","journal-title":"Sci. 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Biol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"e22622","DOI":"10.1371\/journal.pone.0029502","article-title":"Sh3pxd2b mice are a model for craniofacial dysmorphology and otitis media","volume":"6","author":"Yang","year":"2011","journal-title":"PLoS One"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1038\/17812","article-title":"Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2","volume":"397","author":"Yokota","year":"1999","journal-title":"Nature"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1016\/j.ajpath.2012.05.031","article-title":"Pathological features in the LmnaDhe\/+ mutant mouse provide a novel model of human otitis media and laminopathies","volume":"181","author":"Zhang","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.ydbio.2010.10.004","article-title":"Developmental ablation of Id1 and Id3 genes in the vasculature leads to postnatal cardiac phenotypes","volume":"349","author":"Zhao","year":"2011","journal-title":"Dev. Biol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/S0378-5955(99)00003-9","article-title":"Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses","volume":"130","author":"Zheng","year":"1999","journal-title":"Hear. Res."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"eaao2139","DOI":"10.1126\/sciimmunol.aao2139","article-title":"Transcription factor ID2 prevents E proteins from enforcing a na\u00efve T lymphocyte gene program during NK cell development","volume":"3","author":"Zook","year":"2018","journal-title":"Sci. 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