{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:40:59Z","timestamp":1785426059211,"version":"3.56.0"},"reference-count":40,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical University of Bialystok"},{"id":[{"id":"https:\/\/ror.org\/00y4ya841","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tooth agenesis is a common developmental anomaly of the human dentition, ranging from hypodontia to oligodontia, yet its marked phenotypic variability remains insufficiently explained. This review synthesizes developmental and molecular evidence on epithelial\u2013mesenchymal interactions during early odontogenesis and proposes a signaling-threshold framework for human tooth agenesis. We focus on the coordinated roles of Wnt\/\u03b2-catenin, bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and Sonic hedgehog (SHH) pathways and on recurrent disease-associated genes, including MSX1, PAX9, WNT10A, and AXIN2, as quantitative modulators of pathway activity rather than binary determinants of tooth identity. Within this framework, successful tooth initiation may depend on whether integrated signaling output exceeds a field-specific activation threshold within spatially graded developmental regions of the dental arch. Differences in signaling amplitude, duration, and transcriptional responsiveness may therefore account for distal tooth susceptibility, variable penetrance, arch asymmetry, and the broad clinical spectrum from mild hypodontia to severe oligodontia. By integrating molecular genetics with developmental field theory, this model provides a testable systems-level explanation for selective tooth absence and highlights priority directions for future functional and genotype\u2013phenotype studies.<\/jats:p>","DOI":"10.3390\/ijms27104528","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T07:35:43Z","timestamp":1779176143000},"page":"4528","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Signaling-Threshold Framework for Human Tooth Agenesis: Integrating Molecular Genetics with Developmental Field Theory"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5281-0940","authenticated-orcid":false,"given":"Anna Ewa","family":"Kuc","sequence":"first","affiliation":[{"name":"Department of Dentofacial Orthopedics and Orthodontics, Wroclaw Medical University, 50-425 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulina","family":"Kuc","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Medical University of Bialystok, ul. Kili\u0144skiego 1, 15-089 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Kuc","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Medical University of Bialystok, ul. Kili\u0144skiego 1, 15-089 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4326-8907","authenticated-orcid":false,"given":"Magdalena","family":"Sulewska","sequence":"additional","affiliation":[{"name":"Department of Periodontal and Oral Mucosa Diseases, Medical University of Bialystok, ul. Waszyngtona 13, 15-269 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9594-8173","authenticated-orcid":false,"given":"Marzena","family":"Tylicka","sequence":"additional","affiliation":[{"name":"Department of Medical Biophysics, Medical University of Bialystok, ul. Mickiewicza 2a, 15-089 Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2518-0007","authenticated-orcid":false,"given":"Micha\u0142","family":"Sarul","sequence":"additional","affiliation":[{"name":"Department of Integrated Dentistry, Wroclaw Medical University, 50-425 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2530","DOI":"10.1002\/ajmg.a.31360","article-title":"The Genetic Basis of Tooth Development and Dental Defects","volume":"140","author":"Thesleff","year":"2006","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nrg1380","article-title":"The Cutting-Edge of Mammalian Development; How the Embryo Makes Teeth","volume":"5","author":"Tucker","year":"2004","journal-title":"Nat. Rev. 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