{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T03:41:45Z","timestamp":1790480505348,"version":"4.1.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T00:00:00Z","timestamp":1620086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010231","name":"Banting Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010231","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004073","name":"Killam Trusts","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004073","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Many reptiles are able to continuously replace their teeth through life, an ability attributed to the existence of epithelial stem cells. Tooth replacement occurs in a spatially and temporally regulated manner, suggesting the involvement of diffusible factors, potentially over long distances. Here, we locally disrupted tooth replacement in the leopard gecko (<jats:italic>Eublepharis macularius<\/jats:italic>) and followed the recovery of the dentition. We looked at the effects on local patterning and functionally tested whether putative epithelial stem cells can give rise to multiple cell types in the enamel organs of new teeth. Second generation teeth with enamel and dentine were removed from adult geckos. The dental lamina was either left intact or disrupted in order to interfere with local patterning cues. The dentition began to reform by 1 month and was nearly recovered by 2\u20133 months as shown in \u03bcCT scans and eruption of teeth labeled with fluorescent markers. Microscopic analysis showed that the dental lamina was fully healed by 1 month. The deepest parts of the dental lamina retained odontogenic identity as shown by PITX2 staining. A pulse-chase was carried out to label cells that were stimulated to enter the cell cycle and then would carry BrdU forward into subsequent tooth generations. Initially we labeled 70\u201378% of PCNA cells with BrdU. After a 1-month chase, the percentage of BrdU + PCNA labeled cells in the dental lamina had dropped to 10%, consistent with the dilution of the label. There was also a population of single, BrdU-labeled cells present up to 2 months post surgery. These BrdU-labeled cells were almost entirely located in the dental lamina and were the likely progenitor\/stem cells because they had not entered the cell cycle. In contrast fragmented BrdU was seen in the PCNA-positive, proliferating enamel organs. Homeostasis and recovery of the gecko dentition was therefore mediated by a stable population of epithelial stem cells in the dental lamina.<\/jats:p>","DOI":"10.3389\/fphys.2021.576816","type":"journal-article","created":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T05:36:15Z","timestamp":1620020175000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["Tooth Removal in the Leopard Gecko and the de novo Formation of Replacement Teeth"],"prefix":"10.3389","volume":"12","author":[{"given":"Kirstin S.","family":"Brink","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaqu\u00edn Ignacio","family":"Henr\u00edquez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa M.","family":"Grieco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesus Rodolfo","family":"Martin del Campo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joy M.","family":"Richman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1238","DOI":"10.1002\/stem.3042","article-title":"Functionally Distinctive Ptch Receptors Establish Multimodal Hedgehog Signaling in the Tooth Epithelial Stem Cell Niche.","volume":"37","author":"Binder","year":"2019","journal-title":"Stem Cells"},{"key":"B2","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1093\/icb\/icaa099","article-title":"The Effects of Premature Tooth Extraction and Damage on Replacement Timing in the Green Iguana.","volume":"60","author":"Brink","year":"2020","journal-title":"Integr. Comp Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1177\/0022034512442896","article-title":"Early regression of the dental lamina underlies the development of diphyodont dentitions.","volume":"91","author":"Buchtova","year":"2012","journal-title":"J. Dent Res."},{"key":"B4","doi-asserted-by":"crossref","DOI":"10.1242\/dev.164889","article-title":"SOX2 regulation by hedgehog signaling controls adult lingual epithelium homeostasis.","volume":"145","author":"Castillo-Azofeifa","year":"2018","journal-title":"Development"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7998.1966.tb03006.x","article-title":"Tooth Replacement in Slow Worm (Anguis Fragilis).","volume":"150","author":"Cooper","year":"1966","journal-title":"J. Zool."},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aau5484","article-title":"An ancient Turing-like patterning mechanism regulates skin denticle development in sharks.","volume":"4","author":"Cooper","year":"2018","journal-title":"Sci. Adv."},{"key":"B7","first-page":"1","article-title":"Tooth replacement phenomena in the lower vertebrates.","volume":"52","author":"Edmund","year":"1960","journal-title":"Contribut. Life Sci. Div."},{"key":"B8","first-page":"7","article-title":"Sequence and rate of tooth replacement in the Crocodilia.","volume":"56","author":"Edmund","year":"1962","journal-title":"Contribut. Life Sci. Div."},{"key":"B9","first-page":"117","article-title":"\u201cDentition,\u201d in","author":"Edmund","year":"1969","journal-title":"Biology of the Reptilia,. Morphology A"},{"key":"B10","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1002\/jmor.10591","article-title":"Tooth replacement pattern of Coloborhynchus robustus (Pterosauria) from the Lower Cretaceous of Brazil.","volume":"269","author":"Fastnacht","year":"2008","journal-title":"J. Morphol."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7007-6-32","article-title":"A periodic pattern generator for dental diversity.","volume":"6","author":"Fraser","year":"2008","journal-title":"BMC Biol."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.2019.0401","article-title":"The first formed tooth serves as a signalling centre to induce the formation of the dental row in zebrafish.","volume":"286","author":"Gibert","year":"2019","journal-title":"Proc. R Soc. B Biol. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.ceb.2020.12.015","article-title":"Environmental control of lineage plasticity and stem cell memory.","volume":"69","author":"Gola","year":"2021","journal-title":"Curr. Opin. Cell Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1111\/ede.12247","article-title":"Coordination of bilateral tooth replacement in the juvenile gecko is continuous with in ovo patterning.","volume":"20","author":"Grieco","year":"2018","journal-title":"Evol. Dev."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00208","article-title":"Oral Mucosal Epithelial Cells.","volume":"10","author":"Groeger","year":"2019","journal-title":"Front. Immunol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1002\/ar.24014","article-title":"Description of Tooth Ontogeny and Replacement Patterns in a Juvenile Tarbosaurus bataar (Dinosauria: Theropoda) Using CT-Scan Data.","volume":"302","author":"Hanai","year":"2019","journal-title":"Anat. Rec."},{"key":"B17","doi-asserted-by":"publisher","first-page":"3545","DOI":"10.1242\/dev.052415","article-title":"Identification of putative dental epithelial stem cells in a lizard with life-long tooth replacement.","volume":"137","author":"Handrigan","year":"2010","journal-title":"Dev."},{"key":"B18","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1002\/jez.b.21438","article-title":"Unicuspid and bicuspid tooth crown formation in squamates.","volume":"316","author":"Handrigan","year":"2011","journal-title":"J. Exp. Zool. B Mol. Dev. Evol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1083\/jcb.147.1.105","article-title":"Localization of putative stem cells in dental epithelium and their association with Notch and FGF signaling.","volume":"147","author":"Harada","year":"1999","journal-title":"J. Cell Biol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.matbio.2013.02.005","article-title":"Dual functions for WNT5A during cartilage development and in disease.","volume":"32","author":"Hosseini-Farahabadi","year":"2013","journal-title":"Matrix Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1016\/j.cell.2014.02.057","article-title":"Transit-amplifying cells orchestrate stem cell activity and tissue regeneration.","volume":"157","author":"Hsu","year":"2014","journal-title":"Cell"},{"key":"B22","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1111\/j.1439-0426.2012.02002.x","article-title":"The pattern of the lower jaw dentition in farmed Atlantic salmon (Salmo salar): a tool to study mechanisms of tooth replacement?","volume":"28","author":"Huysseune","year":"2012","journal-title":"J. Appl. Ichthyol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1424","DOI":"10.1242\/dev.089599","article-title":"Sox2 marks epithelial competence to generate teeth in mammals and reptiles.","volume":"140","author":"Juuri","year":"2013","journal-title":"Dev."},{"key":"B24","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.devcel.2012.05.012","article-title":"Sox2+ stem cells contribute to all epithelial lineages of the tooth via Sfrp5+ progenitors.","volume":"23","author":"Juuri","year":"2012","journal-title":"Dev. Cell"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.12729","article-title":"Sox2 maintains epithelial cell proliferation in the successional dental lamina.","volume":"53","author":"Kim","year":"2020","journal-title":"Cell Prolif."},{"key":"B26","doi-asserted-by":"publisher","first-page":"176","DOI":"10.2307\/1563746","article-title":"A Long-Term Study of the Tooth Replacement Phenomenon in the Young Green Iguana, Iguana-Iguana.","volume":"18","author":"Kline","year":"1984","journal-title":"J. Herpetol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1002\/jmor.1051860303","article-title":"Tooth Replacement and Growth in the Young Green Iguana, Iguana-Iguana.","volume":"186","author":"Kline","year":"1985","journal-title":"J. Morphol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/0014-4827(86)90520-3","article-title":"Expression of Proliferating Cell Nuclear Antigen (Pcna)\/Cyclin during the Cell-Cycle.","volume":"166","author":"Kurki","year":"1986","journal-title":"Exp. Cell Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"14769","DOI":"10.1073\/pnas.1612354113","article-title":"Sox2+ progenitors in sharks link taste development with the evolution of regenerative teeth from denticles.","volume":"113","author":"Martin","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B30","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1002\/dvdy.21857","article-title":"MicroCT for developmental biology: a versatile tool for high-contrast 3D imaging at histological resolutions.","volume":"238","author":"Metscher","year":"2009","journal-title":"Dev. Dyn."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2927","DOI":"10.1039\/ft9969202927","article-title":"On a dynamic reaction-diffusion mechanism: The spatial patterning of teeth primordia in the alligator.","volume":"92","author":"Murray","year":"1996","journal-title":"J. Chem. Soc. -Faraday Transact."},{"key":"B32","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1038\/225343a0","article-title":"New approach to Zahnreihen.","volume":"225","author":"Osborn","year":"1970","journal-title":"Nature"},{"key":"B33","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1098\/rspb.1971.0097","article-title":"The ontogeny of tooth succession in Lacerta vivipara Jacquin (1787).","volume":"179","author":"Osborn","year":"1971","journal-title":"Proc. R Soc. Lond. B Biol. Sci."},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/bies.201900229","article-title":"The Vertebrate Tooth Row: Is It Initiated by a Single Organizing Tooth?","volume":"42","author":"Sadier","year":"2020","journal-title":"Bioessays"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.47702","article-title":"The alternative regenerative strategy of bearded dragon unveils the key processes underlying vertebrate tooth renewal.","volume":"8","author":"Salomies","year":"2019","journal-title":"Elife"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1102","DOI":"10.1038\/s41556-019-0378-2","article-title":"A large pool of actively cycling progenitors orchestrates self-renewal and injury repair of an ectodermal appendage.","volume":"21","author":"Sharir","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1126\/science.abb6848","article-title":"Tissue regeneration: Reserve or reverse?","volume":"371","author":"Shivdasani","year":"2021","journal-title":"Science"},{"key":"B38","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1111\/j.1469-7998.1987.tb05984.x","article-title":"Development of the Dentition in Alligator-Mississippiensis. Later Development in the Lower Jaws of Embryos, Hatchlings and Young Juveniles.","volume":"212","author":"Westergaard","year":"1987","journal-title":"J. Zool."},{"key":"B39","doi-asserted-by":"crossref","first-page":"E2009","DOI":"10.1073\/pnas.1213202110","article-title":"Specialized stem cell niche enables repetitive renewal of alligator teeth.","volume":"110","author":"Wu","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.03.038","article-title":"Epithelial-Mesenchymal Micro-niches Govern Stem Cell Lineage Choices.","volume":"48","author":"Yang","year":"2017","journal-title":"Cell"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1242\/dev.184754","article-title":"Molecular and cellular mechanisms of tooth development, homeostasis and repair.","volume":"147","author":"Yu","year":"2020","journal-title":"Development"}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.576816\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T05:36:23Z","timestamp":1620020183000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.576816\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,4]]},"references-count":41,"alternative-id":["10.3389\/fphys.2021.576816"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2021.576816","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,4]]},"article-number":"576816"}}