{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T06:35:21Z","timestamp":1791959721773,"version":"4.3.4"},"reference-count":60,"publisher":"National Academy of Sciences","issue":"14","license":[{"start":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T00:00:00Z","timestamp":1743638400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000055","name":"HHS | NIH | National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","award":["1R01DC020268"],"award-info":[{"award-number":["1R01DC020268"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000055","name":"HHS | NIH | National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","award":["T32DC009975"],"award-info":[{"award-number":["T32DC009975"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000055","name":"HHS | NIH | National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","award":["5R25DC019700"],"award-info":[{"award-number":["5R25DC019700"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,4,8]]},"abstract":"<jats:p>\n                    The mature mammalian auditory sensory organ, the organ of Corti (OC), lacks the capacity for regenerating hair cells, leading to permanent hearing impairment. In contrast, the vestibular system has a limited capacity for hair cell regeneration, which we have shown to be further enhanced by inhibiting the Hippo pathway. Here, we demonstrate that, despite similar transcriptional responses, only vestibular and not auditory supporting cells proliferate as a result of Yap activation following Hippo inhibition. Mechanistically, we identify p27\n                    <jats:sup>Kip1<\/jats:sup>\n                    , a cell cycle kinase inhibitor encoded by\n                    <jats:italic>Cdkn1b<\/jats:italic>\n                    , as an additional barrier preventing cell cycle reentry specifically in the OC. We show that while in both systems Yap stimulates p27\n                    <jats:sup>Kip1<\/jats:sup>\n                    degradation through activation of its direct target gene\n                    <jats:italic>Skp2<\/jats:italic>\n                    , this protein-level control is antagonized by an unusually high level of\n                    <jats:italic>Cdkn1b<\/jats:italic>\n                    transcription in the cochlea. Consequently, p27\n                    <jats:sup>Kip1<\/jats:sup>\n                    activity is maintained in the OC even in the presence of constitutively active Yap5SA, counteracting its mitogenic effects. Supporting this model, inactivation of the Hippo pathway in the\n                    <jats:italic>Cdkn1b<\/jats:italic>\n                    -deficient background is sufficient to induce adult auditory supporting cell proliferation in vivo. Furthermore, we show that the synergistic interaction between Hippo and p27\n                    <jats:sup>Kip1<\/jats:sup>\n                    is conserved in the retina where inhibition of both pathways potently induces M\u00fcller glia proliferation and initiates neuronal regeneration. Our work uncovers the molecular mechanism preventing quiescent adult sensory progenitor cells, supporting cells in the ear and M\u00fcller glia in the eye, from reentering the cell cycle after damage\u2014the key step toward sensory receptor regeneration blocked in mammals.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2411313122","type":"journal-article","created":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T23:43:22Z","timestamp":1743723802000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":14,"title":["The Hippo pathway and p27\n                    <sup>Kip1<\/sup>\n                    cooperate to suppress mitotic regeneration in the organ of Corti and the retina"],"prefix":"10.1073","volume":"122","author":[{"given":"Eva","family":"Jahanshir","sequence":"first","affiliation":[{"name":"University of Southern California Caruso Department of Otolaryngology\u2014Head and Neck Surgery, Keck School of Medicine of University of Southern California","place":["Los Angeles"]},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0074-1242","authenticated-orcid":false,"given":"Juan","family":"Llamas","sequence":"additional","affiliation":[{"name":"University of Southern California Caruso Department of Otolaryngology\u2014Head and Neck Surgery, Keck School of Medicine of University of Southern California","place":["Los Angeles"]},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeeun","family":"Kim","sequence":"additional","affiliation":[{"name":"University of Southern California Caruso Department of Otolaryngology\u2014Head and Neck Surgery, Keck School of Medicine of University of Southern California","place":["Los Angeles"]},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Biju","sequence":"additional","affiliation":[{"name":"University of Southern California Caruso Department of Otolaryngology\u2014Head and Neck Surgery, Keck School of Medicine of University of Southern California","place":["Los Angeles"]},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanyukta","family":"Oak","sequence":"additional","affiliation":[{"name":"University of Southern California Caruso Department of Otolaryngology\u2014Head and Neck Surgery, Keck School of Medicine of University of Southern California","place":["Los Angeles"]},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3870-9256","authenticated-orcid":false,"given":"Ksenia","family":"Gnedeva","sequence":"additional","affiliation":[{"name":"University of Southern California Caruso Department of Otolaryngology\u2014Head and Neck Surgery, Keck School of Medicine of University of Southern California","place":["Los Angeles"]},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,4,3]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2021.07.003"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-018-0086-y"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.274027.115"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.015896"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2016.08.004"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2300839120"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1843810"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1602907"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1313192110"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2000175117"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3216"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01119-7"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2019.01.017"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.25681"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-77775-8"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0306-20.2020"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23395-3"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02453"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.126.8.1581"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1709-12.2012"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.24660"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2467"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.19921"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/pnasnexus\/pgae445"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2206113119"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.10085"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-00938-8"},{"key":"e_1_3_4_28_2","first-page":"56648","article-title":"Posterior 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Deposited 28 May 2024."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2411313122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T23:46:25Z","timestamp":1743723985000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2411313122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,3]]},"references-count":60,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2025,4,8]]}},"alternative-id":["10.1073\/pnas.2411313122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2411313122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,3]]},"assertion":[{"value":"2024-06-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2411313122"}}