{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T13:26:04Z","timestamp":1789046764999,"version":"build-2803163510"},"reference-count":61,"publisher":"National Academy of Sciences","issue":"28","license":[{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"HHS | NIH | National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01 DE022503"],"award-info":[{"award-number":["R01 DE022503"]}],"id":[{"id":"10.13039\/100000072","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":[[2025,7,15]]},"abstract":"<jats:p>\n                    Mechanical forces are ubiquitous and essential during vertebrate development, yet how these forces are translated into biochemical signals and regulate development during postnatal organogenesis remains poorly understood. While early embryogenesis relies on cell-autonomous mechanotransduction, the role of sensory innervation\u2014abundant in postnatal stages\u2014has been overlooked. Here, using the postnatal mouse molar development model, a system experiencing sustained mechanical forces and extensive innervation during tooth root formation, we first identify a subpopulation of\n                    <jats:italic toggle=\"yes\">Piezo2<\/jats:italic>\n                    + mechanosensory neurons in the trigeminal ganglia and reveal these neurons specifically detect tooth root-associated mechanical forces and orchestrate tooth root development via paracrine signaling. Critically, we show that\n                    <jats:italic toggle=\"yes\">Piezo2<\/jats:italic>\n                    in neurons\u2014not in dental cells\u2014is essential for tooth root morphogenesis, revealing sensory neurons as unexpected master regulators of mesenchymal cell fate. Mechanistically,\n                    <jats:italic toggle=\"yes\">Piezo2<\/jats:italic>\n                    activation triggers the calcium-dependent secretion of platelet-derived growth factor A, defining the neuronal mechanotransduction pathway that directly converts force into biochemical signals to drive organogenesis. Taken together, our findings demonstrate that\n                    <jats:italic toggle=\"yes\">Piezo2<\/jats:italic>\n                    + mechanosensory neurons primarily orchestrate mechanical-force-regulated processes during postnatal development. The identification of the PIEZO2\u2013calcium\u2013PDGF axis provides important insight into mechanotransduction by introducing sensory neurons as active architects of tissue development. This work establishes a paradigm in developmental biology, revealing how mechanosensation bridges biomechanics and neurobiology to regulate postnatal organogenesis, with implications for tissue regeneration strategies.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2504103122","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T11:39:52Z","timestamp":1751974792000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":9,"title":["<i>Piezo2<\/i>\n                    + mechanosensory neurons orchestrate postnatal development through mechano-chemo-transduction of PDGFA signaling"],"prefix":"10.1073","volume":"122","author":[{"given":"Lin","family":"Meng","sequence":"first","affiliation":[{"name":"Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California","place":["Los Angeles"]},{"name":"The First Outpatient Department, Hospital of Stomatology, Jilin University","place":["Changchun, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jifan","family":"Feng","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingwei","family":"Guo","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sa","family":"Cha","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heliya","family":"Ziaei","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Harouni","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6293-4739","authenticated-orcid":false,"given":"Thach-Vu","family":"Ho","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2477-7247","authenticated-orcid":false,"given":"Yang","family":"Chai","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,7,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-021-00424-z"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2020.11.025"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2021.06.006"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.199826"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.10.008"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2023.01.039"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.4561"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21178-4"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2024.102372"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2021.05.001"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-08097-7"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07237-y"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2023.07.013"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/ccr3.6715"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1597\/07-084"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2013.12.013"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-35977-4"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1741-4520.2012.00371.x"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.03.003"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0185543"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2014.00021"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4162"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature20793"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16971-6"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2830-7"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.07.006"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108964"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.137216"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2011.07.006"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/bies.201800140"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41368-020-00110-4"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01541"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2014.02.029"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.archoralbio.2008.03.004"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.202043"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32490-y"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2023.05.015"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.150136"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13980"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2004.03.007"},{"key":"e_1_3_4_41_2","article-title":"Ror2-mediated non-canonical Wnt signaling regulates Cdc42 and cell proliferation during tooth root development","volume":"148","author":"Ma Y.","year":"2021","unstructured":"Y. Ma, , Ror2-mediated non-canonical Wnt signaling regulates Cdc42 and cell proliferation during tooth root development. 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Meng Bulk RNA-seq analysis of the trigeminal ganglion and molar tooth root at PN6.5 between control and AvCreERT2;Piezo2fl\/fl mice. FaceBase Consortium https:\/\/doi.org\/10.25550\/74-X8CE. Deposited 13 January 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2504103122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T11:39:57Z","timestamp":1751974797000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2504103122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,8]]},"references-count":61,"journal-issue":{"issue":"28","published-print":{"date-parts":[[2025,7,15]]}},"alternative-id":["10.1073\/pnas.2504103122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2504103122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,8]]},"assertion":[{"value":"2025-02-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2504103122"}}