{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T19:45:21Z","timestamp":1775936721402,"version":"3.50.1"},"posted":{"date-parts":[[2025,3,4]]},"group-title":"Developmental Biology","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Hair cells (HCs) within the inner ear cochlea are specialized mechanoreceptors required for hearing. Cochlear HCs are not regenerated in mammals, and their loss is a leading cause of deafness in humans. Cochlear supporting cells (SCs) in newborn mice have the capacity to regenerate HCs, but persistent Notch signaling, presumably activated by SC-specific Notch ligand Jagged1 (JAG1), prevents SCs from converting into HCs. Here, employing an organoid platform, we show that while JAG1 participates in HC-fate repression, JAG1\u2019s primary function is to preserve the \u201cprogenitor-like characteristics\u201d of cochlear SCs. Transcriptomic and mechanistic studies reveal that JAG1\/Notch signaling maintains the expression of progenitor and metabolic genes in cochlear SCs and sustains pro-growth pathways, including PI3K-Akt-mTOR signaling, a function that is mediated by Notch1 and Notch2. Finally, we show that JAG1\/Notch signaling stimulation with JAG1-Fc peptide enhances the HC-forming capacity of cochlear SCs undergoing maturation in cochlear explants and\n                  <jats:italic>in vivo<\/jats:italic>\n                  .\n                <\/jats:p>","DOI":"10.1101\/2025.03.02.640998","type":"posted-content","created":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T05:36:06Z","timestamp":1741152966000},"source":"Crossref","is-referenced-by-count":0,"title":["The Notch ligand Jagged1 plays a dual role in cochlear hair cell regeneration"],"prefix":"10.64898","author":[{"given":"Xiao-Jun","family":"Li","sequence":"first","affiliation":[{"name":"The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Frontier Institute of Science and Technology, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"Morgan","sequence":"additional","affiliation":[{"name":"The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Li","sequence":"additional","affiliation":[{"name":"Frontier Institute of Science and Technology, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wan-Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Frontier Institute of Science and Technology, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Chrysostomou","sequence":"additional","affiliation":[{"name":"The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7424-2112","authenticated-orcid":false,"given":"Angelika","family":"Doetzlhofer","sequence":"additional","affiliation":[{"name":"The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Department of Otolaryngology and Center for Hearing and Balance, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041112092738000_2025.03.02.640998v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.284.5415.770"},{"key":"2026041112092738000_2025.03.02.640998v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.03.045"},{"key":"2026041112092738000_2025.03.02.640998v1.3","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-34436-8_8"},{"key":"2026041112092738000_2025.03.02.640998v1.4","doi-asserted-by":"publisher","DOI":"10.1242\/dev.108100"},{"key":"2026041112092738000_2025.03.02.640998v1.5","doi-asserted-by":"publisher","DOI":"10.1002\/cne.20997"},{"key":"2026041112092738000_2025.03.02.640998v1.6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.0020004"},{"key":"2026041112092738000_2025.03.02.640998v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/nature03487"},{"key":"2026041112092738000_2025.03.02.640998v1.8","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1494-14.2014"},{"key":"2026041112092738000_2025.03.02.640998v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2008.01.006"},{"key":"2026041112092738000_2025.03.02.640998v1.10","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.22169"},{"key":"2026041112092738000_2025.03.02.640998v1.11","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02284"},{"key":"2026041112092738000_2025.03.02.640998v1.12","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.22243"},{"key":"2026041112092738000_2025.03.02.640998v1.13","doi-asserted-by":"publisher","DOI":"10.1007\/s101620010023"},{"key":"2026041112092738000_2025.03.02.640998v1.14","doi-asserted-by":"publisher","DOI":"10.1007\/s10162-009-0162-2"},{"key":"2026041112092738000_2025.03.02.640998v1.15","doi-asserted-by":"publisher","DOI":"10.1186\/1471-213x-8-20"},{"key":"2026041112092738000_2025.03.02.640998v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2011.01.038"},{"key":"2026041112092738000_2025.03.02.640998v1.17","doi-asserted-by":"publisher","DOI":"10.1126\/science.284.5421.1837"},{"key":"2026041112092738000_2025.03.02.640998v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/6804"},{"key":"2026041112092738000_2025.03.02.640998v1.19","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02002"},{"key":"2026041112092738000_2025.03.02.640998v1.20","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3859-05.2006"},{"key":"2026041112092738000_2025.03.02.640998v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2008.11.008"},{"key":"2026041112092738000_2025.03.02.640998v1.22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0073276"},{"key":"2026041112092738000_2025.03.02.640998v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.10.032"},{"key":"2026041112092738000_2025.03.02.640998v1.24","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2015.00110"},{"key":"2026041112092738000_2025.03.02.640998v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4773(99)00066-0"},{"key":"2026041112092738000_2025.03.02.640998v1.26","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1192-20.2020"},{"key":"2026041112092738000_2025.03.02.640998v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-05380-w"},{"key":"2026041112092738000_2025.03.02.640998v1.28","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2000417117"},{"key":"2026041112092738000_2025.03.02.640998v1.29","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abj7651"},{"key":"2026041112092738000_2025.03.02.640998v1.30","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202256562"},{"key":"2026041112092738000_2025.03.02.640998v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.01.066"},{"key":"2026041112092738000_2025.03.02.640998v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108646"},{"key":"2026041112092738000_2025.03.02.640998v1.33","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2022.1031989"},{"key":"2026041112092738000_2025.03.02.640998v1.34","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1690-08.2008"},{"key":"2026041112092738000_2025.03.02.640998v1.35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008254"},{"key":"2026041112092738000_2025.03.02.640998v1.36","doi-asserted-by":"publisher","DOI":"10.1242\/dev.127.21.4551"},{"key":"2026041112092738000_2025.03.02.640998v1.37","doi-asserted-by":"publisher","DOI":"10.1038\/nature04849"},{"key":"2026041112092738000_2025.03.02.640998v1.38","doi-asserted-by":"publisher","DOI":"10.1038\/srep23293"},{"key":"2026041112092738000_2025.03.02.640998v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16113-y"},{"key":"2026041112092738000_2025.03.02.640998v1.40","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0075521"},{"key":"2026041112092738000_2025.03.02.640998v1.41","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1210159109"},{"key":"2026041112092738000_2025.03.02.640998v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09234-6"},{"key":"2026041112092738000_2025.03.02.640998v1.43","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.17.9.5426"},{"key":"2026041112092738000_2025.03.02.640998v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2008.120"},{"key":"2026041112092738000_2025.03.02.640998v1.45","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44059-4"},{"key":"2026041112092738000_2025.03.02.640998v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80515-2"},{"key":"2026041112092738000_2025.03.02.640998v1.47","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V91.11.4084"},{"key":"2026041112092738000_2025.03.02.640998v1.48","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M412891200"},{"key":"2026041112092738000_2025.03.02.640998v1.49","doi-asserted-by":"publisher","DOI":"10.1038\/srep19484"},{"key":"2026041112092738000_2025.03.02.640998v1.50","doi-asserted-by":"publisher","DOI":"10.1002\/gene.10241"},{"key":"2026041112092738000_2025.03.02.640998v1.51","doi-asserted-by":"publisher","DOI":"10.1172\/JCI97248"},{"key":"2026041112092738000_2025.03.02.640998v1.52","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0239-05.2005"},{"key":"2026041112092738000_2025.03.02.640998v1.53","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5420-11.2012"},{"key":"2026041112092738000_2025.03.02.640998v1.54","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11687-8"},{"key":"2026041112092738000_2025.03.02.640998v1.55","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-45784-0"},{"key":"2026041112092738000_2025.03.02.640998v1.56","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkm477"},{"key":"2026041112092738000_2025.03.02.640998v1.57","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-021-03493-w"},{"key":"2026041112092738000_2025.03.02.640998v1.58","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2022.100170"},{"key":"2026041112092738000_2025.03.02.640998v1.59","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.106046"},{"key":"2026041112092738000_2025.03.02.640998v1.60","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3150-12.2013"},{"key":"2026041112092738000_2025.03.02.640998v1.61","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13157-7"},{"key":"2026041112092738000_2025.03.02.640998v1.62","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202203557"},{"key":"2026041112092738000_2025.03.02.640998v1.63","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2410829122"},{"key":"2026041112092738000_2025.03.02.640998v1.64","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.19921"},{"key":"2026041112092738000_2025.03.02.640998v1.65","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4372-07.2008"},{"key":"2026041112092738000_2025.03.02.640998v1.66","doi-asserted-by":"publisher","DOI":"10.1242\/dev.060566"},{"key":"2026041112092738000_2025.03.02.640998v1.67","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2015.05.025"},{"key":"2026041112092738000_2025.03.02.640998v1.68","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.44431"},{"key":"2026041112092738000_2025.03.02.640998v1.69","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.43736"},{"key":"2026041112092738000_2025.03.02.640998v1.70","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2008.10.033"},{"key":"2026041112092738000_2025.03.02.640998v1.71","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2018.00120"},{"key":"2026041112092738000_2025.03.02.640998v1.72","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.79712"},{"key":"2026041112092738000_2025.03.02.640998v1.73","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20976"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.03.02.640998","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T19:09:32Z","timestamp":1775934572000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.03.02.640998"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,4]]},"references-count":73,"URL":"https:\/\/doi.org\/10.1101\/2025.03.02.640998","relation":{},"subject":[],"published":{"date-parts":[[2025,3,4]]},"subtype":"preprint"}}