{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:12:24Z","timestamp":1788415944607,"version":"build-2803163510"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Mutations in\n                      <jats:italic>ALX1<\/jats:italic>\n                      cause frontonasal dysplasia type 3 (FND3), a congenital craniofacial disorder characterized by severe abnormalities of the frontonasal and midfacial structures. However, the role of\n                      <jats:italic>ALX1<\/jats:italic>\n                      in tooth development remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated the function of\n                      <jats:italic>Alx1<\/jats:italic>\n                      during mouse incisor morphogenesis using a neural crest-specific conditional knockout model. Histological, molecular, and transcriptomic analyses were performed to assess incisor morphogenesis, enamel knot formation, odontogenic gene expression, and signaling pathway activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Mutant embryos exhibited complete agenesis of maxillary incisors and impaired development of mandibular incisors. Although tooth initiation was preserved, mutant maxillary incisors failed to progress through the bud-to-cap transition and lacked a discernible enamel knot. Transcriptomic profiling of E13.5 dental mesenchyme revealed alterations in odontogenic gene programs, including genes associated with BMP and Wnt signaling pathways. Consistent with these findings, expression of\n                      <jats:italic>Bmp4<\/jats:italic>\n                      and\n                      <jats:italic>Msx1<\/jats:italic>\n                      was markedly reduced, accompanied by impaired enamel knot-associated\n                      <jats:italic>Shh<\/jats:italic>\n                      expression. In parallel, canonical Wnt signaling activity, as indicated by active \u03b2-catenin and LEF1, was attenuated in mutant incisors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      These findings identify\n                      <jats:italic>Alx1<\/jats:italic>\n                      as an essential regulator of enamel knot formation and incisor morphogenesis, demonstrate a critical role for\n                      <jats:italic>Alx1<\/jats:italic>\n                      in maintaining odontogenic signaling during early tooth development, and provide new mechanistic insight into the dental abnormalities associated with\n                      <jats:italic>ALX1<\/jats:italic>\n                      deficiency.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphys.2026.1939236","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:14:19Z","timestamp":1788412459000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Alx1 is required for enamel knot formation during incisor morphogenesis"],"prefix":"10.3389","volume":"17","author":[{"given":"Xi","family":"Zheng","sequence":"first","affiliation":[{"name":"Fujian Key Laboratory of Oral Diseases & Clinical Research Center for Oral Tissue Deficiency Diseases of Fujian Province & Fujian Provincial Engineering Research Center of Oral Biomaterial, School and Hospital of Stomatology, Fujian Medical University","place":["Fuzhou, China"]},{"name":"Fujian Key Laboratory of Developmental and Neural Biology, College of Life Sciences, Fujian Normal University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbin","family":"Lu","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Developmental and Neural Biology, College of Life Sciences, Fujian Normal University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiyang","family":"Chen","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Developmental and Neural Biology, College of Life Sciences, Fujian Normal University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Xu","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Developmental and Neural Biology, College of Life Sciences, Fujian Normal University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chensheng","family":"Lin","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Developmental and Neural Biology, College of Life Sciences, Fujian Normal University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Lv","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Developmental and Neural Biology, College of Life Sciences, Fujian Normal University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanding","family":"Zhang","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Developmental and Neural Biology, College of Life Sciences, Fujian Normal University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefeng","family":"Hu","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Developmental and Neural Biology, College of Life Sciences, Fujian Normal University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minkui","family":"Lin","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Oral Diseases & Clinical Research Center for Oral Tissue Deficiency Diseases of Fujian Province & Fujian Provincial Engineering Research Center of Oral Biomaterial, School and Hospital of Stomatology, Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1002\/stem.2917","article-title":"Concise review: cellular and molecular mechanisms regulation of tooth initiation","volume":"37","author":"Balic","year":"2019","journal-title":"Stem Cells"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1200","DOI":"10.1177\/0022034517719264","article-title":"Grainyhead-like transcription factors in craniofacial development","volume":"96","author":"Carpinelli","year":"2017","journal-title":"J. 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