{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T21:07:19Z","timestamp":1790024839634,"version":"4.0.1"},"reference-count":135,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T00:00:00Z","timestamp":1696982400000},"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","doi-asserted-by":"publisher","award":["RGPIN 05364-2019"],"award-info":[{"award-number":["RGPIN 05364-2019"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tooth number anomalies, including hyperdontia and hypodontia, are common congenital dental problems in the dental clinic. The precise number of teeth in a dentition is essential for proper speech, mastication, and aesthetics. Teeth are ectodermal organs that develop from the interaction of a thickened epithelium (dental placode) with the neural-crest-derived ectomesenchyme. There is extensive histological, molecular, and genetic evidence regarding how the tooth number is regulated in this serial process, but there is currently no universal classification for tooth number abnormalities. In this review, we propose a novel regulatory network for the tooth number based on the inherent dentition formation process. This network includes three intuitive directions: the development of a single tooth, the formation of a single dentition with elongation of the continual lamina, and tooth replacement with the development of the successional lamina. This article summarizes recent reports on early tooth development and provides an analytical framework to classify future relevant experiments.<\/jats:p>","DOI":"10.3390\/ijms242015061","type":"journal-article","created":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T02:11:01Z","timestamp":1696990261000},"page":"15061","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Count Me in, Count Me out: Regulation of the Tooth Number via Three Directional Developmental Patterns"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9326-7053","authenticated-orcid":false,"given":"Zheng","family":"Fang","sequence":"first","affiliation":[{"name":"Department of Oral Biology, Dr. Gerald Niznick College of Dentistry, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E0W2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0279-1857","authenticated-orcid":false,"given":"Devi","family":"Atukorallaya","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, Dr. Gerald Niznick College of Dentistry, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E0W2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Shah, A., Gill, D.S., Tredwin, C., and Naini, F.B. (2008). Diagnosis and Management of Supernumerary Teeth. Dent. Update, 35.","DOI":"10.12968\/denu.2008.35.8.510"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1046\/j.1365-263X.2002.00366.x","article-title":"Supernumerary Teeth: Review of the Literature and a Survey of 152 Cases","volume":"12","author":"Rajab","year":"2002","journal-title":"Int. J. Paediatr. Dent."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1111\/j.1600-0528.1987.tb00524.x","article-title":"Hypodontia and Hyperdontia of Permanent Teeth in Hong Kong Schoolchildren","volume":"15","author":"Davis","year":"1987","journal-title":"Community Dent. Oral Epidemiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"221","DOI":"10.4103\/0972-0707.85791","article-title":"Management of Supernumerary Teeth","volume":"14","author":"Parolia","year":"2011","journal-title":"J. Conserv. Dent."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3109\/00016358509046490","article-title":"Characteristics of Premaxillary Hyperodontia. A Radiographic Study","volume":"43","author":"Hurlen","year":"1985","journal-title":"Acta Odontol. Scand."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"345","DOI":"10.31486\/toj.18.0060","article-title":"Diagnosis of Tooth Agenesis in Childhood and Risk for Neoplasms in Adulthood","volume":"18","author":"Ritwik","year":"2018","journal-title":"Ochsner J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1055\/s-0036-1592421","article-title":"Genetic Basis of Nonsyndromic and Syndromic Tooth Agenesis","volume":"5","author":"Ye","year":"2016","journal-title":"J. Pediatr. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1177\/0022034517750109","article-title":"Rare and Common Variants Conferring Risk of Tooth Agenesis","volume":"97","author":"Jonsson","year":"2018","journal-title":"J. Dent. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1083\/jcb.201512074","article-title":"Early Epithelial Signaling Center Governs Tooth Budding Morphogenesis","volume":"214","author":"Ahtiainen","year":"2016","journal-title":"J. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1002\/dvdy.23952","article-title":"Expression of Foxi3 Is Regulated by Ectodysplasin in Skin Appendage Placodes","volume":"242","author":"Shirokova","year":"2013","journal-title":"Dev. Dyn."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1006\/dbio.1999.9547","article-title":"Antagonistic Signals between BMP4 and FGF8 Define the Expression of Pitx1 and Pitx2 in Mouse Tooth-Forming Anlage","volume":"217","author":"Zhang","year":"2000","journal-title":"Dev. Biol."},{"key":"ref_12","first-page":"1424","article-title":"Sox2 Marks Epithelial Competence to Generate Teeth in Mammals and Reptiles","volume":"140","author":"Juuri","year":"2013","journal-title":"Dev. Camb. Engl."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/ng0494-348","article-title":"Msx1 Deficient Mice Exhibit Cleft Palate and Abnormalities of Craniofacial and Tooth Development","volume":"6","author":"Satokata","year":"1994","journal-title":"Nat. Genet."},{"key":"ref_14","unstructured":"Lewington, J. (2007). Ferret Husbandry, Medicine and Surgery, Elsevier."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.mod.2014.09.002","article-title":"Spatial and Temporal Events in Tooth Development of Astyanax Mexicanus","volume":"134","author":"Atukorala","year":"2014","journal-title":"Mech. Dev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1177\/0022034517720158","article-title":"The Biology Underlying Abnormalities of Tooth Number in Humans","volume":"96","author":"Juuri","year":"2017","journal-title":"J. Dent. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"18627","DOI":"10.1073\/pnas.0607289103","article-title":"Continuous Tooth Generation in Mouse Is Induced by Activated Epithelial Wnt\/\u03b2-Catenin Signaling","volume":"103","author":"Birchmeier","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","first-page":"dev158048","article-title":"Mesenchymal Wnt\/\u03b2-Catenin Signaling Limits Tooth Number","volume":"145","author":"Balic","year":"2018","journal-title":"Dev. Camb. Engl."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/S0012-1606(03)00325-7","article-title":"Mechanisms of Ectodermal Organogenesis","volume":"262","author":"Pispa","year":"2003","journal-title":"Dev. Biol."},{"key":"ref_20","first-page":"32","article-title":"Initiation of Teeth from the Dental Lamina in the Ferret","volume":"87","author":"Jussila","year":"2014","journal-title":"Differ. Res. Biol. Divers."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1387\/ijdb.170051gc","article-title":"Contribution of Cranial Neural Crest Cells to Mouse Skull Development","volume":"61","author":"Wu","year":"2017","journal-title":"Int. J. Dev. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1111\/joa.12180","article-title":"Patterns of Morphological Variation in Enamel\u2013Dentin Junction and Outer Enamel Surface of Human Molars","volume":"224","author":"Morita","year":"2014","journal-title":"J. Anat."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1177\/0022034519869307","article-title":"Molar Bud-to-Cap Transition Is Proliferation Independent","volume":"98","author":"Yamada","year":"2019","journal-title":"J. Dent. Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Phillips, H.M., Papoutsi, T., Soenen, H., Ybot-Gonzalez, P., Henderson, D.J., and Chaudhry, B. (2012). Neural Crest Cell Survival Is Dependent on Rho Kinase and Is Required for Development of the Mid Face in Mouse Embryos. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0037685"},{"key":"ref_25","first-page":"dev186023","article-title":"Pitx2-Sox2-Lef1 Interactions Specify Progenitor Oral\/Dental Epithelial Cell Signaling Centers","volume":"147","author":"Yu","year":"2020","journal-title":"Dev. Camb. Engl."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1006\/dbio.1997.8672","article-title":"Mouse Otlx2\/RIEG Expression in the Odontogenic Epithelium Precedes Tooth Initiation and Requires Mesenchyme-Derived Signals for Its Maintenance","volume":"189","author":"Mucchielli","year":"1997","journal-title":"Dev. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1111\/adj.12130","article-title":"Three-Dimensional Analysis of the Early Development of the Dentition","volume":"59","author":"Peterkova","year":"2014","journal-title":"Aust. Dent. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.ydbio.2018.07.008","article-title":"Genetic Linkage between Altered Tooth and Eye Development in Lens-Ablated Astyanax Mexicanus","volume":"441","author":"Atukorala","year":"2018","journal-title":"Dev. Biol."},{"key":"ref_29","first-page":"3127","article-title":"Developmental Genetic Mechanisms of Evolutionary Tooth Loss in Cypriniform Fishes","volume":"133","author":"Stock","year":"2006","journal-title":"Dev. Camb. Engl."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2311","DOI":"10.1098\/rspb.2004.2878","article-title":"Conserved Deployment of Genes during Odontogenesis across Osteichthyans","volume":"271","author":"Fraser","year":"2004","journal-title":"Proc. R. Soc. B Biol. Sci."},{"key":"ref_31","first-page":"670","article-title":"Epithelial Stratification and Placode Invagination Are Separable Functions in Early Morphogenesis of the Molar Tooth","volume":"143","author":"Li","year":"2016","journal-title":"Dev. Camb. Engl."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1038\/s41467-020-16247-z","article-title":"Epithelial Invagination by a Vertical Telescoping Cell Movement in Mammalian Salivary Glands and Teeth","volume":"11","author":"Li","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/cr.2008.302","article-title":"Signaling Cross-Talk between TGF-\u03b2\/BMP and Other Pathways","volume":"19","author":"Guo","year":"2009","journal-title":"Cell Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1177\/0022034512448660","article-title":"BMP Activity Is Required for Tooth Development from the Lamina to Bud Stage","volume":"91","author":"Wang","year":"2012","journal-title":"J. Dent. Res."},{"key":"ref_35","first-page":"533","article-title":"Interactions between Bmp-4 and Msx-1 Act to Restrict Gene Expression to Odontogenic Mesenchyme","volume":"212","author":"Tucker","year":"1998","journal-title":"Dev. Dyn. Off. Publ. Am. Assoc. Anat."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/eos.12390","article-title":"Homeobox Protein MSX-1 Inhibits Expression of Bone Morphogenetic Protein 2, Bone Morphogenetic Protein 4, and Lymphoid Enhancer-Binding Factor 1 via Wnt\/\u03b2-Catenin Signaling to Prevent Differentiation of Dental Mesenchymal Cells during the Late Bell Stage","volume":"126","author":"Feng","year":"2018","journal-title":"Eur. J. Oral Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.ydbio.2016.10.001","article-title":"Bmp4-Msx1 Signaling and Osr2 Control Tooth Organogenesis through Antagonistic Regulation of Secreted Wnt Antagonists","volume":"420","author":"Jia","year":"2016","journal-title":"Dev. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4711","DOI":"10.1242\/dev.127.21.4711","article-title":"BMP4 Rescues a Non-Cell-Autonomous Function of Msx1 in Tooth Development","volume":"127","author":"Bei","year":"2000","journal-title":"Development"},{"key":"ref_39","first-page":"3035","article-title":"Msx1 Controls Inductive Signaling in Mammalian Tooth Morphogenesis","volume":"122","author":"Chen","year":"1996","journal-title":"Dev. Camb. Engl."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"203763","DOI":"10.1016\/j.cdev.2021.203763","article-title":"The Regulation of Msx1 by BMP4\/pSmad1\/5 Signaling Is Mediated by Importin7 in Dental Mesenchymal Cells","volume":"169","author":"She","year":"2022","journal-title":"Cells Dev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2735","DOI":"10.1101\/gad.12.17.2735","article-title":"Pax9-Deficient Mice Lack Pharyngeal Pouch Derivatives and Teeth and Exhibit Craniofacial and Limb Abnormalities","volume":"12","author":"Peters","year":"1998","journal-title":"Genes Dev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.jdsr.2017.08.001","article-title":"A Review on Non-Syndromic Tooth Agenesis Associated with PAX9 Mutations","volume":"54","author":"Fauzi","year":"2018","journal-title":"Jpn. Dent. Sci. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/71634","article-title":"Mutation of PAX9 Is Associated with Oligodontia","volume":"24","author":"Stockton","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3605","DOI":"10.1093\/hmg\/ddi388","article-title":"Reduction of Pax9 Gene Dosage in an Allelic Series of Mouse Mutants Causes Hypodontia and Oligodontia","volume":"14","author":"Kist","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.ydbio.2010.01.031","article-title":"Genetic Interactions between Pax9 and Msx1 Regulate Lip Development and Several Stages of Tooth Morphogenesis","volume":"340","author":"Nakatomi","year":"2010","journal-title":"Dev. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"18363","DOI":"10.1074\/jbc.M601543200","article-title":"Functional Consequences of Interactions between Pax9 and Msx1 Genes in Normal and Abnormal Tooth Development","volume":"281","author":"Ogawa","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2863","DOI":"10.1093\/hmg\/ddp221","article-title":"Pathogenic Mechanisms of Tooth Agenesis Linked to Paired Domain Mutations in Human PAX9","volume":"18","author":"Wang","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1177\/0022034510387430","article-title":"Msx1 Mutations: How Do They Cause Tooth Agenesis?","volume":"90","author":"Wang","year":"2011","journal-title":"J. Dent. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1111\/bjd.20601","article-title":"WNT10A, Dermatology and Dentistry","volume":"185","author":"Doolan","year":"2021","journal-title":"Br. J. Dermatol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/S1534-5807(02)00167-3","article-title":"WNT Signals Are Required for the Initiation of Hair Follicle Development","volume":"2","author":"Andl","year":"2002","journal-title":"Dev. Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.ydbio.2007.10.016","article-title":"Wnt\/Beta-Catenin Signaling Directs Multiple Stages of Tooth Morphogenesis","volume":"313","author":"Liu","year":"2008","journal-title":"Dev. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1177\/00220345211070583","article-title":"MSX1 Drives Tooth Morphogenesis Through Controlling Wnt Signaling Activity","volume":"101","author":"Lee","year":"2022","journal-title":"J. Dent. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1002\/ajmg.a.60682","article-title":"Distinct Impacts of Bi-Allelic WNT10A Mutations on the Permanent and Primary Dentitions in Odonto-Onycho-Dermal Dysplasia","volume":"179","author":"Yu","year":"2019","journal-title":"Am. J. Med. Genet. A."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10266-013-0142-1","article-title":"Fibroblast Growth Factor Signaling in Mammalian Tooth Development","volume":"102","author":"Li","year":"2014","journal-title":"Odontology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1111\/j.1469-7580.2011.01352.x","article-title":"Expression of Fibroblast Growth Factors (Fgfs) in Murine Tooth Development","volume":"218","author":"Porntaveetus","year":"2011","journal-title":"J. Anat."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1002\/jez.b.21274","article-title":"Epithelial-Specific Requirement of FGFR2 Signaling during Tooth and Palate Development","volume":"312B","author":"Hosokawa","year":"2009","journal-title":"J. Exp. Zool. Part B Mol. Dev. Evol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Wang, X.-P., Suomalainen, M., Felszeghy, S., Zelarayan, L.C., Alonso, M.T., Plikus, M.V., Maas, R.L., Chuong, C.-M., Schimmang, T., and Thesleff, I. (2007). An Integrated Gene Regulatory Network Controls Stem Cell Proliferation in Teeth. PLoS Biol., 5.","DOI":"10.1371\/journal.pbio.0050159"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3173","DOI":"10.1101\/gad.1035602","article-title":"FGF4, a Direct Target of LEF1 and Wnt Signaling, Can Rescue the Arrest of Tooth Organogenesis in Lef1\u2212\/\u2212 Mice","volume":"16","author":"Kratochwil","year":"2002","journal-title":"Genes Dev."},{"key":"ref_59","first-page":"1939","article-title":"Apc Inhibition of Wnt Signaling Regulates Supernumerary Tooth Formation during Embryogenesis and throughout Adulthood","volume":"136","author":"Wang","year":"2009","journal-title":"Dev. Camb. Engl."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1974","DOI":"10.1177\/00220345010800110501","article-title":"Sonic Hedgehog Regulates Epithelial Proliferation and Cell Survival in the Developing Tooth Germ","volume":"80","author":"Cobourne","year":"2001","journal-title":"J. Dent. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.3389\/fphys.2022.1033130","article-title":"Eda Controls the Size of the Enamel Knot during Incisor Development","volume":"13","author":"Horakova","year":"2023","journal-title":"Front. Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4907","DOI":"10.1242\/dev.01377","article-title":"Ectodysplasin A1 Promotes Placodal Cell Fate during Early Morphogenesis of Ectodermal Appendages","volume":"131","author":"Mustonen","year":"2004","journal-title":"Development"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/adj.12102","article-title":"Current Understanding of the Process of Tooth Formation: Transfer from the Laboratory to the Clinic","volume":"59","author":"Thesleff","year":"2014","journal-title":"Aust. Dent. J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1168538","DOI":"10.3389\/fgene.2023.1168538","article-title":"The EDA\/EDAR\/NF-\u03baB Pathway in Non-Syndromic Tooth Agenesis: A Genetic Perspective","volume":"14","author":"Gao","year":"2023","journal-title":"Front. Genet."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e1555","DOI":"10.1002\/mgg3.1555","article-title":"Missense Mutations in EDA and EDAR Genes Cause Dominant Syndromic Tooth Agenesis","volume":"9","author":"Andreoni","year":"2021","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1006\/dbio.1999.9514","article-title":"Cusp Patterning Defect in Tabby Mouse Teeth and Its Partial Rescue by FGF","volume":"216","author":"Pispa","year":"1999","journal-title":"Dev. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"581843","DOI":"10.3389\/fphys.2020.581843","article-title":"Pax9\u2019s Interaction With the Ectodysplasin Signaling Pathway During the Patterning of Dentition","volume":"11","author":"Jia","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1177\/0022034513487210","article-title":"Non-Syndromic Tooth Agenesis Associated with a Nonsense Mutation in Ectodysplasin-A (EDA)","volume":"92","author":"Nikopensius","year":"2013","journal-title":"J. Dent. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1111\/odi.14402","article-title":"Gene Mutations and Chromosomal Abnormalities in Syndromes with Tooth Agenesis","volume":"29","author":"Lan","year":"2023","journal-title":"Oral Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.archoralbio.2004.11.010","article-title":"Characteristic Tissue Interaction of the Diastema Region in Mice","volume":"50","author":"Yamamoto","year":"2005","journal-title":"Arch. Oral Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3221","DOI":"10.1242\/dev.054668","article-title":"Inhibition of Wnt Signaling by Wise (Sostdc1) and Negative Feedback from Shh Controls Tooth Number and Patterning","volume":"137","author":"Ahn","year":"2010","journal-title":"Development"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1177\/154405910808700412","article-title":"Mesenchyme Is Responsible for Tooth Suppression in the Mouse Lower Diastema","volume":"87","author":"Yuan","year":"2008","journal-title":"J. Dent. Res."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Yoshinaga, K., Yasue, A., Mitsui, S.N., Minegishi, Y., Oyadomari, S., Imoto, I., and Tanaka, E. (2023). Effects of Wnt10a and Wnt10b Double Mutations on Tooth Development. Genes, 14.","DOI":"10.3390\/genes14020340"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.devcel.2006.05.014","article-title":"Sprouty Genes Control Diastema Tooth Development via Bidirectional Antagonism of Epithelial-Mesenchymal FGF Signaling","volume":"11","author":"Klein","year":"2006","journal-title":"Dev. Cell"},{"key":"ref_75","first-page":"393","article-title":"Tinkering with the Inductive Mesenchyme: Sostdc1 Uncovers the Role of Dental Mesenchyme in Limiting Tooth Induction","volume":"136","author":"Munne","year":"2009","journal-title":"Dev. Camb. Engl."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/BF00305754","article-title":"Development of Human First and Second Permanent Molar, with Special Reference to the Distal Protion of the Dental Lamina","volume":"155","year":"1979","journal-title":"Anat. Embryol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Wang, F., Li, Y., Wu, X., Yang, M., Cong, W., Fan, Z., Wang, J., Zhang, C., Du, J., and Wang, S. (2017). Transcriptome Analysis of Coding and Long Non-Coding RNAs Highlights the Regulatory Network of Cascade Initiation of Permanent Molars in Miniature Pigs. BMC Genom., 18.","DOI":"10.1186\/s12864-017-3546-4"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1111\/odi.12126","article-title":"Morphology and Chronology of Diphyodont Dentition in Miniature Pigs, Sus Scrofa","volume":"20","author":"Wang","year":"2014","journal-title":"Oral Dis."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1002\/ar.24819","article-title":"Tooth Replacement and Attachment Morphology in the Pacific Leaping Blenny, Alticus Arnoldorum (Blenniiformes: Blenniidae: Salariini) with a Discussion on Tooth Function","volume":"305","author":"Williams","year":"2022","journal-title":"Anat. Rec."},{"key":"ref_80","unstructured":"G\u00f3mez-Gil, D.F., Orjuela-V\u00e1squez, M.C., Pino-Duque, M., Pino-Araujo, A., S\u00e1nchez-Garz\u00f3n, J., G\u00f3mez-Gil, D.F., Orjuela-V\u00e1squez, M.C., Pino-Duque, M., Pino-Araujo, A., and S\u00e1nchez-Garz\u00f3n, J. (2022). Embryology Update, IntechOpen."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Ko, D., Kelly, T., Thompson, L., Uppal, J.K., Rostampour, N., Webb, M.A., Zhu, N., Belev, G., Mondal, P., and Cooper, D.M.L. (2021). Timing of Mouse Molar Formation Is Independent of Jaw Length Including Retromolar Space. J. Dev. Biol., 9.","DOI":"10.3390\/jdb9010008"},{"key":"ref_82","unstructured":"Kozawa, Y., Mishima, H., Suzuki, K., and Ferguson, M. (2001, January 6\u201320). Dental Formula of Elephant by the Development of Tooth Germ. Proceedings of the World of Elephants: Rome, First International Congress, Rome, Italy."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1242\/bio.013672","article-title":"Epithelial Topography for Repetitive Tooth Formation","volume":"4","author":"Gaete","year":"2015","journal-title":"Biol. Open"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1007\/s10914-021-09597-y","article-title":"From Embryo to Adult: The Complete Development and Unusual Replacement of the Dentition of the Tammar Wallaby (Macropus Eugenii)","volume":"29","author":"Nasrullah","year":"2022","journal-title":"J. Mamm. Evol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"996","DOI":"10.3389\/fphys.2020.00996","article-title":"Balance Between Tooth Size and Tooth Number Is Controlled by Hyaluronan","volume":"11","author":"Contreras","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.semcdb.2013.12.013","article-title":"Evolution and Developmental Diversity of Tooth Regeneration","volume":"25\u201326","author":"Tucker","year":"2014","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"E4425","DOI":"10.1073\/pnas.1702909114","article-title":"Spatially Restricted Dental Regeneration Drives Pufferfish Beak Development","volume":"114","author":"Thiery","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e12729","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":"ref_89","doi-asserted-by":"crossref","first-page":"450","DOI":"10.14219\/jada.archive.2003.0194","article-title":"The Unresolved Problem of the Third Molar: Would People Be Better off without It?","volume":"134","author":"Silvestri","year":"2003","journal-title":"J. Am. Dent. Assoc."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"59","DOI":"10.2535\/ofaj1936.61.1_59","article-title":"A Histological Study of the Development of Human Dental Laminae","volume":"61","author":"Nagahama","year":"1984","journal-title":"Okajimas Folia Anat. Jpn."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.joms.2011.03.063","article-title":"Prevalence and Management of Fourth Molars: A Retrospective Study and Literature Review","volume":"70","author":"Shahzad","year":"2012","journal-title":"J. Oral Maxillofac. Surg."},{"key":"ref_92","first-page":"104","article-title":"Presence of the fourth molar. Literature review","volume":"22","author":"Mosqueyra","year":"2018","journal-title":"Rev. Odontol. Mex."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1111\/eos.12095","article-title":"Expression of the Stem Cell Marker, SOX2, in Ameloblastoma and Dental Epithelium","volume":"121","author":"Juuri","year":"2013","journal-title":"Eur. J. Oral Sci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/nyas.14988","article-title":"PAX9 Mutations and Genetic Synergism in Familial Tooth Agenesis","volume":"1524","author":"Chu","year":"2023","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1002\/jez.b.21093","article-title":"Phylogenetic Memory of Developing Mammalian Dentition","volume":"306","author":"Peterkova","year":"2006","journal-title":"J. Exp. Zool. B Mol. Dev. Evol."},{"key":"ref_96","first-page":"233","article-title":"The Presence of Rudimentary Odontogenic Structures in the Mouse Embryonic Mandible Requires Reinterpretation of Developmental Control of First Lower Molar Histomorphogenesis","volume":"44","author":"Viriot","year":"2000","journal-title":"Int. J. Dev. Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1080\/03008200290001168","article-title":"Evolutionary Implications of the Occurrence of Two Vestigial Tooth Germs During Early Odontogenesis in the Mouse Lower Jaw","volume":"43","author":"Viriot","year":"2002","journal-title":"Connect. Tissue Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/j.1600-0722.2011.00838.x","article-title":"Morphogenesis and Bone Integration of the Mouse Mandibular Third Molar","volume":"119","author":"Chlastakova","year":"2011","journal-title":"Eur. J. Oral Sci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"15397","DOI":"10.1038\/ncomms15397","article-title":"WNT10A Mutation Causes Ectodermal Dysplasia by Impairing Progenitor Cell Proliferation and KLF4-Mediated Differentiation","volume":"8","author":"Xu","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1111\/j.1525-142X.2005.05048.x","article-title":"Morphoregulation of Teeth: Modulating the Number, Size, Shape and Differentiation by Tuning Bmp Activity","volume":"7","author":"Plikus","year":"2005","journal-title":"Evol. Dev."},{"key":"ref_101","unstructured":"Bertonnier-Brouty, L. (2019). Dental Development and Replacement in Lagomorpha. [Ph.D. Thesis, Universit\u00e9 de Lyon]."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Bertonnier-Brouty, L., Viriot, L., Joly, T., and Charles, C. (2020). Morphological Features of Tooth Development and Replacement in the Rabbit Oryctolagus Cuniculus. Arch. Oral Biol., 109.","DOI":"10.1016\/j.archoralbio.2019.104576"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1002\/jez.b.21275","article-title":"The Role of the Dental Lamina in Mammalian Tooth Replacement","volume":"312B","author":"Tummers","year":"2009","journal-title":"J. Exp. Zool. B Mol. Dev. Evol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1007\/s10735-016-9684-1","article-title":"Hyaluronan and Hyaluronan Synthases Expression and Localization in Embryonic Mouse Molars","volume":"47","author":"Yang","year":"2016","journal-title":"J. Mol. Histol."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Dosed\u011blov\u00e1, H., Dumkov\u00e1, J., Lesot, H., Glocov\u00e1, K., Kunov\u00e1, M., Tucker, A.S., Vesel\u00e1, I., Krej\u010d\u00ed, P., Tich\u00fd, F., and Hampl, A. (2015). Fate of the Molar Dental Lamina in the Monophyodont Mouse. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0127543"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/j.1469-7580.2012.01531.x","article-title":"Tooth Development in a Model Reptile: Functional and Null Generation Teeth in the Gecko Paroedura Picta","volume":"221","author":"Zahradnicek","year":"2012","journal-title":"J. Anat."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1002\/jmor.20919","article-title":"Tooth Development and Replacement in the Atlantic Cutlassfish, Trichiurus Lepturus, with Comparisons to Other Scombroidei","volume":"280","author":"Bemis","year":"2019","journal-title":"J. Morphol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1387\/ijdb.052098ah","article-title":"Formation of a Successional Dental Lamina in the Zebrafish (Danio Rerio): Support for a Local Control of Replacement Tooth Initiation","volume":"50","author":"Huysseune","year":"2004","journal-title":"Int. J. Dev. Biol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"dev171363","DOI":"10.1242\/dev.171363","article-title":"Revitalising the Rudimentary Replacement Dentition in the Mouse","volume":"146","author":"Popa","year":"2019","journal-title":"Development"},{"key":"ref_110","first-page":"450","article-title":"Supernumerary Premolars: A Literature Review","volume":"26","author":"Solares","year":"2004","journal-title":"Pediatr. Dent."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/ijos.2013.36","article-title":"Biology of Tooth Replacement in Amniotes","volume":"5","author":"Whitlock","year":"2013","journal-title":"Int. J. Oral Sci."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.ydbio.2010.09.003","article-title":"A Network of Wnt, Hedgehog and BMP Signaling Pathways Regulates Tooth Replacement in Snakes","volume":"348","author":"Handrigan","year":"2010","journal-title":"Dev. Biol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"220345231182052","DOI":"10.1177\/00220345231182052","article-title":"Fibulin-1 Regulates Initiation of Successional Dental Lamina","volume":"102","author":"Li","year":"2023","journal-title":"J. Dent. Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1002\/dvdy.436","article-title":"Revitalizing Mouse Diphyodontic Dentition Formation by Inhibiting the Sonic Hedgehog Signaling Pathway","volume":"251","author":"Mao","year":"2022","journal-title":"Dev. Dyn."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1177\/0022034518811322","article-title":"Temporal Control of WNT Activity Regulates Tooth Number in Fish","volume":"98","author":"Shim","year":"2019","journal-title":"J. Dent. Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1177\/0022034519858282","article-title":"Third Dentition Is the Main Cause of Premolar Supernumerary Tooth Formation","volume":"98","author":"Kiso","year":"2019","journal-title":"J. Dent. Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"S34","DOI":"10.1016\/j.archoralbio.2008.06.011","article-title":"Morphogenetic Fields within the Human Dentition: A New, Clinically Relevant Synthesis of an Old Concept","volume":"54","author":"Townsend","year":"2009","journal-title":"Arch. Oral Biol."},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Bateson, W. (1894). Materials for the Study of Variation: Treated with Especial Regard to Discontinuity in the Origin of Species, Macmillan and Company.","DOI":"10.5962\/bhl.title.21037"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1469-7998.1939.tb00021.x","article-title":"Studies of the Mammalian Dentition.\u2013Differentiation of the Post-Canine Dentition","volume":"B109","author":"Butler","year":"1939","journal-title":"Proc. Zool. Soc. Lond."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"676","DOI":"10.14219\/jada.archive.1945.0112","article-title":"The Changing Dentition of Man","volume":"32","author":"Dahlberg","year":"1945","journal-title":"J. Am. Dent. Assoc."},{"key":"ref_121","unstructured":"Dahlberg, A.A. (1949). The Dentition of the American Indian. Pap. Phys. Anthropol. Am. Indians, 138\u2013176."},{"key":"ref_122","unstructured":"Osborn, J.W. (1978). Morphogenetic Gradients: Field versus Clones. Dev. Funct. Evol. Teeth, 171\u2013202."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/s41368-021-00135-3","article-title":"Analyses of Oligodontia Phenotypes and Genetic Etiologies","volume":"13","author":"Zhou","year":"2021","journal-title":"Int. J. Oral Sci."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1177\/0022034518777460","article-title":"Patterns of Dental Agenesis Highlight the Nature of the Causative Mutated Genes","volume":"97","author":"Fournier","year":"2018","journal-title":"J. Dent. Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"e73173","DOI":"10.7554\/eLife.73173","article-title":"An Epithelial Signalling Centre in Sharks Supports Homology of Tooth Morphogenesis in Vertebrates","volume":"11","author":"Thiery","year":"2022","journal-title":"eLife"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1177\/0022034519872679","article-title":"Mesenchymal Sufu Regulates Development of Mandibular Molars via Shh Signaling","volume":"98","author":"Li","year":"2019","journal-title":"J. Dent. Res."},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Hu, X., Zhang, S., Chen, G., Lin, C., Huang, Z., Chen, Y., and Zhang, Y. (2013). Expression of SHH Signaling Molecules in the Developing Human Primary Dentition. BMC Dev. Biol., 13.","DOI":"10.1186\/1471-213X-13-11"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.reth.2023.01.004","article-title":"Advances in Tooth Agenesis and Tooth Regeneration","volume":"22","author":"Ravi","year":"2023","journal-title":"Regen. Ther."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1126\/science.1167418","article-title":"Antagonistic Actions of Msx1 and Osr2 Pattern Mammalian Teeth into a Single Row","volume":"323","author":"Zhang","year":"2009","journal-title":"Science"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1002\/mgg3.111","article-title":"Taurodontism, Variations in Tooth Number, and Misshapened Crowns in Wnt10a Null Mice and Human Kindreds","volume":"3","author":"Yang","year":"2015","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"Edmund, A.G., and Museum, R.O. (1960). Tooth Replacement Phenomena in the Lower Vertebrates, Royal Ontario Museum.","DOI":"10.5962\/bhl.title.52196"},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Sadier, A., Jackman, W.R., Laudet, V., and Gibert, Y. (2020). The Vertebrate Tooth Row: Is It Initiated by a Single Organizing Tooth?. BioEssays, 42.","DOI":"10.1002\/bies.201900229"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s13005-021-00283-1","article-title":"Expression of SOX2 and OCT4 in Odontogenic Cysts and Tumors","volume":"17","author":"Phattarataratip","year":"2021","journal-title":"Head Face Med."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1515\/mamm.1984.48.1.105","article-title":"Horizontal Tooth Replacement in the Amazonian Manatee (Trichechus inunguis)","volume":"48","author":"Domning","year":"1984","journal-title":"Mammalia"},{"key":"ref_135","unstructured":"Woodard, N. (2020). Are Florida Manatees (Trichechus Manatus Latirostris) Wearing Their Teeth Beyond Functionality? Interspecific and Intraspecific Mesowear in Manatees. [Honors Thesis, Andrews University]."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15061\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:04:39Z","timestamp":1760130279000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15061"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,11]]},"references-count":135,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms242015061"],"URL":"https:\/\/doi.org\/10.3390\/ijms242015061","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,11]]}}}