{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:42:08Z","timestamp":1760150528355,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,12,4]],"date-time":"2023-12-04T00:00:00Z","timestamp":1701648000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grants-in-Aid for Specially Promoted Research","award":["20H05628","22K18399","21H04839","21K09569"],"award-info":[{"award-number":["20H05628","22K18399","21H04839","21K09569"]}]},{"name":"Grants-in-Aid for Challenging Research (Pioneering)","award":["20H05628","22K18399","21H04839","21K09569"],"award-info":[{"award-number":["20H05628","22K18399","21H04839","21K09569"]}]},{"name":"Japan Society for the Promotion of Science, Takeda Science Foundation, and Taiju Life Social Welfare Foundation","award":["20H05628","22K18399","21H04839","21K09569"],"award-info":[{"award-number":["20H05628","22K18399","21H04839","21K09569"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mammalian auditory hair cells transduce sound-evoked traveling waves in the cochlea into nerve stimuli, which are essential for hearing function. Pillar cells located between the inner and outer hair cells are involved in the formation of the tunnel of Corti, which incorporates outer-hair-cell-driven fluid oscillation and basilar membrane movement, leading to the fine-tuned frequency-specific perception of sounds by the inner hair cells. However, the detailed molecular mechanism underlying the development and maintenance of pillar cells remains to be elucidated. In this study, we examined the expression and function of brain-specific angiogenesis inhibitor 3 (Bai3), an adhesion G-protein-coupled receptor, in the cochlea. We found that Bai3 was expressed in hair cells in neonatal mice and pillar cells in adult mice, and, interestingly, Bai3 knockout mice revealed the abnormal formation of pillar cells, with the elevation of the hearing threshold in a frequency-dependent manner. Furthermore, old Bai3 knockout mice showed the degeneration of hair cells and spiral ganglion neurons in the basal turn. The results suggest that Bai3 plays a crucial role in the development and\/or maintenance of pillar cells, which, in turn, are necessary for normal hearing function. Our results may contribute to understanding the mechanisms of hearing loss in human patients.<\/jats:p>","DOI":"10.3390\/ijms242317092","type":"journal-article","created":{"date-parts":[[2023,12,4]],"date-time":"2023-12-04T03:40:58Z","timestamp":1701661258000},"page":"17092","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Brain-Specific Angiogenesis Inhibitor 3 Is Expressed in the Cochlea and Is Necessary for Hearing Function in Mice"],"prefix":"10.3390","volume":"24","author":[{"given":"Chika","family":"Saegusa","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics, Kitasato University School of Medicine, Kanagawa 252-0374, Japan"},{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2092-5775","authenticated-orcid":false,"given":"Wataru","family":"Kakegawa","sequence":"additional","affiliation":[{"name":"Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eriko","family":"Miura","sequence":"additional","affiliation":[{"name":"Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahiro","family":"Aimi","sequence":"additional","affiliation":[{"name":"Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sachiyo","family":"Mogi","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Kitasato University, Kanagawa 252-0374, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuhiko","family":"Harada","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, International University of Health and Welfare, Shizuoka 413-0012, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taku","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Kitasato University, Kanagawa 252-0374, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5750-3544","authenticated-orcid":false,"given":"Michisuke","family":"Yuzaki","sequence":"additional","affiliation":[{"name":"Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5317-0885","authenticated-orcid":false,"given":"Masato","family":"Fujioka","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Kitasato University School of Medicine, Kanagawa 252-0374, Japan"},{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan"},{"name":"Clinical and Translational Research Center, Keio University Hospital, Tokyo 162-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1038\/nrd4533","article-title":"New treatment options for hearing loss","volume":"14","author":"Muller","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1146\/annurev.neuro.25.112701.142849","article-title":"Auditory system development: Primary auditory neurons and their targets","volume":"25","author":"Rubel","year":"2002","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/ng0496-390","article-title":"Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3","volume":"12","author":"Colvin","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1016\/j.devcel.2021.04.017","article-title":"Cochlear supporting cells require GAS2 for cytoskeletal architecture and hearing","volume":"56","author":"Chen","year":"2021","journal-title":"Dev. Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"8301737","DOI":"10.1155\/2016\/8301737","article-title":"Emerging Roles of BAI Adhesion-GPCRs in Synapse Development and Plasticity","volume":"2016","author":"Duman","year":"2016","journal-title":"Neural Plast."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1073\/pnas.1019577108","article-title":"The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins","volume":"108","author":"Bolliger","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.neuron.2014.12.020","article-title":"Anterograde C1ql1 signaling is required in order to determine and maintain a single-winner climbing fiber in the mouse cerebellum","volume":"85","author":"Kakegawa","year":"2015","journal-title":"Neuron"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.celrep.2015.01.034","article-title":"The Secreted Protein C1QL1 and Its Receptor BAI3 Control the Synaptic Connectivity of Excitatory Inputs Converging on Cerebellar Purkinje Cells","volume":"10","author":"Sigoillot","year":"2015","journal-title":"Cell Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.neuron.2020.04.004","article-title":"A Synaptic Circuit Required for Acquisition but Not Recall of Social Transmission of Food Preference","volume":"107","author":"Wang","year":"2020","journal-title":"Neuron"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"18086","DOI":"10.1074\/jbc.RA118.005403","article-title":"Complement 1q-like-3 protein inhibits insulin secretion from pancreatic beta-cells via the cell adhesion G protein-coupled receptor BAI3","volume":"293","author":"Gupta","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4470","DOI":"10.1038\/s41467-018-06897-5","article-title":"Spatiotemporal regulation of the GPCR activity of BAI3 by C1qL4 and Stabilin-2 controls myoblast fusion","volume":"9","author":"Hamoud","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4837","DOI":"10.1091\/mbc.e08-04-0345","article-title":"An alpha-helical extension of the ELMO1 pleckstrin homology domain mediates direct interaction to DOCK180 and is critical in Rac signaling","volume":"19","author":"Komander","year":"2008","journal-title":"Mol. Biol. Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3745","DOI":"10.1073\/pnas.1313886111","article-title":"G-protein coupled receptor BAI3 promotes myoblast fusion in vertebrates","volume":"111","author":"Hamoud","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1038\/mp.2013.46","article-title":"The adhesion-GPCR BAI3, a gene linked to psychiatric disorders, regulates dendrite morphogenesis in neurons","volume":"18","author":"Lanoue","year":"2013","journal-title":"Mol. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6366","DOI":"10.1523\/JNEUROSCI.5126-14.2015","article-title":"Gene Expression by Mouse Inner Ear Hair Cells during Development","volume":"35","author":"Scheffer","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Biswas, J., Pijewski, R.S., Makol, R., Miramontes, T.G., Thompson, B.L., Kresic, L.C., Burghard, A.L., Oliver, D.L., and Martinelli, D.C. (2021). C1ql1 is expressed in adult outer hair cells of the cochlea in a tonotopic gradient. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0251412"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"713651","DOI":"10.3389\/fncel.2021.713651","article-title":"Deletion of C1ql1 Causes Hearing Loss and Abnormal Auditory Nerve Fibers in the Mouse Cochlea","volume":"15","author":"Qi","year":"2021","journal-title":"Front. Cell Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1083\/jcb.201001138","article-title":"Review series: The cell biology of hearing","volume":"190","author":"Schwander","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"107926","DOI":"10.1016\/j.heares.2020.107926","article-title":"753A > G genome editing of a Cdh23(ahl) allele delays age-related hearing loss and degeneration of cochlear hair cells in C57BL\/6J mice","volume":"389","author":"Yasuda","year":"2020","journal-title":"Hear. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/0378-5955(86)90061-4","article-title":"Cytoskeletal organization in the supporting cell of the guinea pig organ of Corti","volume":"24","author":"Arima","year":"1986","journal-title":"Hear. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1242\/dev.073734","article-title":"Cytoskeletal changes in actin and microtubules underlie the developing surface mechanical properties of sensory and supporting cells in the mouse cochlea","volume":"139","author":"Szarama","year":"2012","journal-title":"Development"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3284","DOI":"10.1529\/biophysj.106.084087","article-title":"Evidence for outer hair cell driven oscillatory fluid flow in the tunnel of corti","volume":"92","author":"Karavitaki","year":"2007","journal-title":"Biophys. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3109\/00016487309121476","article-title":"Anatomy and physiology of the onset of auditory function","volume":"76","author":"Pujol","year":"1973","journal-title":"Acta Otolaryngol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"214","DOI":"10.4161\/bioa.22332","article-title":"Fibroblast growth factor receptor 3 regulates microtubule formation and cell surface mechanical properties in the developing organ of Corti","volume":"2","author":"Szarama","year":"2012","journal-title":"Bioarchitecture"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/j.neuroscience.2008.08.027","article-title":"Postnatal development of the organ of Corti in dominant-negative Gjb2 transgenic mice","volume":"156","author":"Inoshita","year":"2008","journal-title":"Neuroscience"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"286","DOI":"10.3109\/00016489109137389","article-title":"Microtubules of guinea pig cochlear epithelial cells","volume":"111","author":"Kikuchi","year":"1991","journal-title":"Acta Otolaryngol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zetes, D.E., Tolomeo, J.A., and Holley, M.C. (2012). Structure and mechanics of supporting cells in the guinea pig organ of Corti. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049338"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2889","DOI":"10.1152\/jn.90637.2008","article-title":"Threshold tuning curves of chinchilla auditory-nerve fibers. I. Dependence on characteristic frequency and relation to the magnitudes of cochlear vibrations","volume":"100","author":"Temchin","year":"2008","journal-title":"J. Neurophysiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.febslet.2004.06.011","article-title":"Expression of brain-specific angiogenesis inhibitor 3 (BAI3) in normal brain and implications for BAI3 in ischemia-induced brain angiogenesis and malignant glioma","volume":"569","author":"Kee","year":"2004","journal-title":"FEBS Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1002\/ajmg.b.30436","article-title":"Addiction molecular genetics: 639,401 SNP whole genome association identifies many \u201ccell adhesion\u201d genes","volume":"141B","author":"Liu","year":"2006","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1093\/schbul\/sbn076","article-title":"The genetics of symptom-based phenotypes: Toward a molecular classification of schizophrenia","volume":"34","author":"DeRosse","year":"2008","journal-title":"Schizophr. Bull."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.schres.2012.05.015","article-title":"Identification and characterization of three inherited genomic copy number variations associated with familial schizophrenia","volume":"139","author":"Liao","year":"2012","journal-title":"Schizophr. Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"McCarthy, M.J., Nievergelt, C.M., Kelsoe, J.R., and Welsh, D.K. (2012). A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0032091"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1038\/s41431-018-0321-1","article-title":"Biallelic intragenic duplication in ADGRB3 (BAI3) gene associated with intellectual disability, cerebellar atrophy, and behavioral disorder","volume":"27","author":"Scuderi","year":"2019","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/j.bbrc.2020.10.073","article-title":"Deficiency of large tumor suppressor kinase 1 causes congenital hearing loss associated with cochlear abnormalities in mice","volume":"534","author":"Nishiyama","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/17092\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:37:15Z","timestamp":1760132235000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/17092"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,4]]},"references-count":35,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ijms242317092"],"URL":"https:\/\/doi.org\/10.3390\/ijms242317092","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,12,4]]}}}