{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:30:07Z","timestamp":1792650607151,"version":"4.5.0"},"reference-count":21,"publisher":"National Academy of Sciences","issue":"2","license":[{"start":{"date-parts":[[2018,12,3]],"date-time":"2018-12-03T00:00:00Z","timestamp":1543795200000},"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":["DE027421"],"award-info":[{"award-number":["DE027421"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"HHS | NIH | National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["DE026666"],"award-info":[{"award-number":["DE026666"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005648","name":"American Association of Orthodontists Foundation","doi-asserted-by":"publisher","award":["Postdoctoral Research Award"],"award-info":[{"award-number":["Postdoctoral Research Award"]}],"id":[{"id":"10.13039\/100005648","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":[[2019,1,8]]},"abstract":"<jats:p>\n                    Formation of functional skeletal tissues requires highly organized steps of mesenchymal progenitor cell differentiation. The dental follicle (DF) surrounding the developing tooth harbors mesenchymal progenitor cells for various differentiated cells constituting the tooth root\u2013bone interface and coordinates tooth eruption in a manner dependent on signaling by parathyroid hormone-related peptide (PTHrP) and the PTH\/PTHrP receptor (PPR). However, the identity of mesenchymal progenitor cells in the DF and how they are regulated by PTHrP-PPR signaling remain unknown. Here, we show that the PTHrP-PPR autocrine signal maintains physiological cell fates of DF mesenchymal progenitor cells to establish the functional periodontal attachment apparatus and orchestrates tooth eruption. A single-cell RNA-seq analysis revealed cellular heterogeneity of PTHrP\n                    <jats:sup>+<\/jats:sup>\n                    cells, wherein PTHrP\n                    <jats:sup>+<\/jats:sup>\n                    DF subpopulations abundantly express PPR. Cell lineage analysis using tamoxifen-inducible\n                    <jats:italic>PTHrP-creER<\/jats:italic>\n                    mice revealed that PTHrP\n                    <jats:sup>+<\/jats:sup>\n                    DF cells differentiate into cementoblasts on the acellular cementum, periodontal ligament cells, and alveolar cryptal bone osteoblasts during tooth root formation. PPR deficiency induced a cell fate shift of PTHrP\n                    <jats:sup>+<\/jats:sup>\n                    DF mesenchymal progenitor cells to nonphysiological cementoblast-like cells precociously forming the cellular cementum on the root surface associated with up-regulation of\n                    <jats:italic>Mef2c<\/jats:italic>\n                    and matrix proteins, resulting in loss of the proper periodontal attachment apparatus and primary failure of tooth eruption, closely resembling human genetic conditions caused by PPR mutations. These findings reveal a unique mechanism whereby proper cell fates of mesenchymal progenitor cells are tightly maintained by an autocrine system mediated by PTHrP-PPR signaling to achieve functional formation of skeletal tissues.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1810200115","type":"journal-article","created":{"date-parts":[[2018,12,3]],"date-time":"2018-12-03T20:16:31Z","timestamp":1543868191000},"page":"575-580","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":141,"title":["Autocrine regulation of mesenchymal progenitor cell fates orchestrates tooth eruption"],"prefix":"10.1073","volume":"116","author":[{"given":"Akira","family":"Takahashi","sequence":"first","affiliation":[{"name":"Department of Orthodontics and Pediatric Dentistry, University of Michigan School of Dentistry, Ann Arbor, MI 48109;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mizuki","family":"Nagata","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Pediatric Dentistry, University of Michigan School of Dentistry, Ann Arbor, MI 48109;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditi","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Pediatric Dentistry, University of Michigan School of Dentistry, Ann Arbor, MI 48109;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Matsushita","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Pediatric Dentistry, University of Michigan School of Dentistry, Ann Arbor, MI 48109;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsutaro","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, Showa University School of Dentistry, 142-8555 Tokyo, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Mizuhashi","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Pediatric Dentistry, University of Michigan School of Dentistry, Ann Arbor, MI 48109;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koutaro","family":"Maki","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, Showa University School of Dentistry, 142-8555 Tokyo, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio C.","family":"Ruellas","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Pediatric Dentistry, University of Michigan School of Dentistry, Ann Arbor, MI 48109;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia S.","family":"Cevidanes","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Pediatric Dentistry, University of Michigan School of Dentistry, Ann Arbor, MI 48109;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry M.","family":"Kronenberg","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3771-8230","authenticated-orcid":false,"given":"Noriaki","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Pediatric Dentistry, University of Michigan School of Dentistry, Ann Arbor, MI 48109;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0358-1897","authenticated-orcid":false,"given":"Wanida","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Pediatric Dentistry, University of Michigan School of Dentistry, Ann Arbor, MI 48109;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2018,12,3]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.gde.2016.06.012","article-title":"Bone repair and stem cells","volume":"40","author":"Ono N","year":"2016","unstructured":"N Ono, HM Kronenberg, Bone repair and stem cells. Curr Opin Genet Dev 40, 103\u2013107 (2016).","journal-title":"Curr Opin Genet Dev"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.cell.2007.08.025","article-title":"Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment","volume":"131","author":"Sacchetti B","year":"2007","unstructured":"B Sacchetti, , Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324\u2013336 (2007).","journal-title":"Cell"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/s41586-018-0662-5","article-title":"Resting zone of the growth plate houses a unique class of skeletal stem cells","volume":"563","author":"Mizuhashi K","year":"2018","unstructured":"K Mizuhashi, , Resting zone of the growth plate houses a unique class of skeletal stem cells. Nature 563, 254\u2013258 (2018).","journal-title":"Nature"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/ncb3139","article-title":"The suture provides a niche for mesenchymal stem cells of craniofacial bones","volume":"17","author":"Zhao H","year":"2015","unstructured":"H Zhao, , The suture provides a niche for mesenchymal stem cells of craniofacial bones. Nat Cell Biol 17, 386\u2013396 (2015).","journal-title":"Nat Cell Biol"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"11846","DOI":"10.1073\/pnas.95.20.11846","article-title":"Parathyroid hormone-related protein is required for tooth eruption","volume":"95","author":"Philbrick WM","year":"1998","unstructured":"WM Philbrick, BE Dreyer, IA Nakchbandi, AC Karaplis, Parathyroid hormone-related protein is required for tooth eruption. Proc Natl Acad Sci USA 95, 11846\u201311851 (1998).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"11277","DOI":"10.1038\/ncomms11277","article-title":"Parathyroid hormone receptor signalling in osterix-expressing mesenchymal progenitors is essential for tooth root formation","volume":"7","author":"Ono W","year":"2016","unstructured":"W Ono, N Sakagami, S Nishimori, N Ono, HM Kronenberg, Parathyroid hormone receptor signalling in osterix-expressing mesenchymal progenitors is essential for tooth root formation. Nat Commun 7, 11277 (2016).","journal-title":"Nat Commun"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"160.e1","DOI":"10.1016\/j.ajodo.2009.10.019","article-title":"Primary failure of eruption and PTH1R: The importance of a genetic diagnosis for orthodontic treatment planning","volume":"137","author":"Frazier-Bowers SA","year":"2010","unstructured":"SA Frazier-Bowers, D Simmons, JT Wright, WR Proffit, JL Ackerman, Primary failure of eruption and PTH1R: The importance of a genetic diagnosis for orthodontic treatment planning. Am J Orthod Dentofacial Orthop 137, 160.e1\u2013160.e7; discussion 160\u2013161 (2010).","journal-title":"Am J Orthod Dentofacial Orthop"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.ajhg.2008.11.006","article-title":"PTHR1 loss-of-function mutations in familial, nonsyndromic primary failure of tooth eruption","volume":"83","author":"Decker E","year":"2008","unstructured":"E Decker, , PTHR1 loss-of-function mutations in familial, nonsyndromic primary failure of tooth eruption. Am J Hum Genet 83, 781\u2013786 (2008).","journal-title":"Am J Hum Genet"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1002\/jbmr.385","article-title":"Exome resequencing combined with linkage analysis identifies novel PTH1R variants in primary failure of tooth eruption in Japanese","volume":"26","author":"Yamaguchi T","year":"2011","unstructured":"T Yamaguchi, , Exome resequencing combined with linkage analysis identifies novel PTH1R variants in primary failure of tooth eruption in Japanese. J Bone Miner Res 26, 1655\u20131661 (2011).","journal-title":"J Bone Miner Res"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"e74601","DOI":"10.1371\/journal.pone.0074601","article-title":"Identification of six novel PTH1R mutations in families with a history of primary failure of tooth eruption","volume":"8","author":"Risom L","year":"2013","unstructured":"L Risom, , Identification of six novel PTH1R mutations in families with a history of primary failure of tooth eruption. PLoS One 8, e74601 (2013).","journal-title":"PLoS One"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.archoralbio.2016.03.012","article-title":"A novel homozygous PTH1R variant identified through whole-exome sequencing further expands the clinical spectrum of primary failure of tooth eruption in a consanguineous Saudi family","volume":"67","author":"Jelani M","year":"2016","unstructured":"M Jelani, , A novel homozygous PTH1R variant identified through whole-exome sequencing further expands the clinical spectrum of primary failure of tooth eruption in a consanguineous Saudi family. 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Gene 404, 70\u201379 (2007).","journal-title":"Gene"},{"key":"e_1_3_4_14_2","first-page":"313","article-title":"The transcription factor mohawk homeobox regulates homeostasis of the periodontal ligament","volume":"144","author":"Koda N","year":"2017","unstructured":"N Koda, , The transcription factor mohawk homeobox regulates homeostasis of the periodontal ligament. Development 144, 313\u2013320 (2017).","journal-title":"Development"},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.cell.2018.05.061","article-title":"Recovering gene interactions from single-cell data using data diffusion","volume":"174","author":"van Dijk D","year":"2018","unstructured":"D van Dijk, , Recovering gene interactions from single-cell data using data diffusion. 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J Oral Pathol 9, 189\u2013200 (1980).","journal-title":"J Oral Pathol"},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1177\/0022034512474469","article-title":"Tooth eruption without roots","volume":"92","author":"Wang XP","year":"2013","unstructured":"XP Wang, Tooth eruption without roots. J Dent Res 92, 212\u2013214 (2013).","journal-title":"J Dent Res"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.1810200115","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1810200115","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T08:34:51Z","timestamp":1775291691000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1810200115"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,3]]},"references-count":21,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2019,1,8]]}},"alternative-id":["10.1073\/pnas.1810200115"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1810200115","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,3]]},"assertion":[{"value":"2018-12-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}