{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T21:26:33Z","timestamp":1793568393956,"version":"4.5.0"},"reference-count":39,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100001824","name":"Grantov\u00e1 Agentura \u010cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["21-04178S"],"award-info":[{"award-number":["21-04178S"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/W00240X\/1"],"award-info":[{"award-number":["BB\/W00240X\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Dent Res"],"abstract":"<jats:p>\n                    Primary cilia are microtubule-based organelles protruding from the surface of mammalian cells, which function as hubs for transducing both biochemical signals (such as Hedgehog) and mechanical force. Defects in cilia are associated with a group of genetic disorders called ciliopathies that disrupt the normal development of multiple organs, including the craniofacial skeleton. One such example is Ellis\u2013van Creveld (EvC) syndrome, a ciliopathy mainly caused by mutations in\n                    <jats:italic toggle=\"yes\">EVC<\/jats:italic>\n                    (EvC ciliary complex subunit1), a key component of the primary cilium essential for the transduction of Hedgehog signaling. Patients with EvC syndrome exhibit a wide spectrum of clinical phenotypes related to multisystemic involvement, including oral defects such as malformations of the teeth, oral vestibule, and ectopic frenula. These distinctive oral defects play a crucial role in the initial diagnosis. The oral vestibule and associated frenula are formed from an embryonic structure, known as the vestibular lamina (VL), which forms closely associated with the dental lamina that forms the teeth. Here we reveal the developmental mechanisms underlying the oral defects in EvC syndrome using\n                    <jats:italic toggle=\"yes\">Evc<\/jats:italic>\n                    knockout mice.\n                    <jats:italic toggle=\"yes\">Evc<\/jats:italic>\n                    mutants exhibited defects in teeth, frenula, and the oral vestibule, mirroring the oral traits of patients with EvC syndrome. A defect in proliferation, and downregulation of\n                    <jats:italic toggle=\"yes\">Gli1<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Sostdc1<\/jats:italic>\n                    during initial outgrowth, led to a shortened VL, although postnatal differentiation and opening of the VL was normal. In some mutants, the VL branched and formed an ectopic tooth germ, which could be partially mimicked by the overexpression of Wnt signaling in the VL. Notably, we observed both upregulation and downregulation of\n                    <jats:italic toggle=\"yes\">Gli1<\/jats:italic>\n                    expression, which was time and tissue specific, suggesting dynamic dysregulation of the normal GLIActivator and GLIRepressor balance. These findings provide novel insights into the underlying etiology of EvC syndrome and other ciliopathies and emphasize that structures developing in close proximity can exhibit divergent responses to the same mutation.\n                  <\/jats:p>","DOI":"10.1177\/00220345261430674","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T06:51:29Z","timestamp":1774939889000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Aberrant Proliferation and Cell Fate Underlie Oral Defects in a Mouse Model of EvC Syndrome"],"prefix":"10.1177","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2087-4843","authenticated-orcid":false,"given":"T.","family":"Qiu","sequence":"first","affiliation":[{"name":"Centre for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral and Craniofacial Sciences, King\u2019s College London, Guy\u2019s Hospital, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6346-6671","authenticated-orcid":false,"given":"M.","family":"Hovorakova","sequence":"additional","affiliation":[{"name":"Institute of Histology and Embryology, First Faculty of Medicine, Charles University in Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Peters","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8871-6094","authenticated-orcid":false,"given":"A.S.","family":"Tucker","sequence":"additional","affiliation":[{"name":"Centre for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral and Craniofacial Sciences, King\u2019s College London, Guy\u2019s Hospital, London, UK"},{"name":"Institute of Histology and Embryology, First Faculty of Medicine, Charles University in Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"e_1_3_3_2_1","doi-asserted-by":"crossref","unstructured":"Asrar H Fons JM Tucker AS. 2025. Vascular invasion of the dental epithelium is essential for ameloblasts. J Dent Res. 104(13):1547\u20131555. https:\/\/doi.org\/10.1177\/00220345251341850","DOI":"10.1177\/00220345251341850"},{"key":"e_1_3_3_3_1","doi-asserted-by":"crossref","unstructured":"Berbari NF O\u2019Connor AK Haycraft CJ Yoder BK. 2009. The primary cilium as a complex signaling center. Curr Biol. 19(13):R526\u2013R535. https:\/\/doi.org\/10.1016\/j.cub.2009.05.025","DOI":"10.1016\/j.cub.2009.05.025"},{"key":"e_1_3_3_4_1","doi-asserted-by":"crossref","unstructured":"Blair HJ et al. 2011. Evc2 is a positive modulator of Hedgehog signalling that interacts with Evc at the cilia membrane and is also found in the nucleus. BMC Biol. 9:14. https:\/\/doi.org\/10.1186\/1741-7007-9-14","DOI":"10.1186\/1741-7007-9-14"},{"key":"e_1_3_3_5_1","doi-asserted-by":"crossref","unstructured":"Brooks EC et al. 2021. Mutation in the ciliary protein C2CD3 reveals organ-specific mechanisms of Hedgehog signal transduction in avian embryos. J Dev Biol. 9(2):12. https:\/\/doi.org\/10.3390\/jdb9020012","DOI":"10.3390\/jdb9020012"},{"key":"e_1_3_3_6_1","doi-asserted-by":"crossref","unstructured":"Bruel AL et al. 2017. Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes. J Med Genet. 54(6):371\u2013380. https:\/\/doi.org\/10.1136\/jmedgenet-2016-104436","DOI":"10.1136\/jmedgenet-2016-104436"},{"key":"e_1_3_3_7_1","doi-asserted-by":"crossref","unstructured":"Bruel AL et al. 2018. INTU-related oral-facial-digital syndrome type VI: a confirmatory report. Clin Genet. 93(6):1205\u20131209. https:\/\/doi.org\/10.1111\/cge.13238","DOI":"10.1111\/cge.13238"},{"key":"e_1_3_3_8_1","doi-asserted-by":"crossref","unstructured":"Caparros-Martin JA et al. 2013. The ciliary Evc\/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu\/Gli3 dissociation and Gli3 trafficking in primary cilia. Hum Mol Genet. 22(1):124\u2013139. https:\/\/doi.org\/10.1093\/hmg\/dds409","DOI":"10.1093\/hmg\/dds409"},{"key":"e_1_3_3_9_1","doi-asserted-by":"crossref","unstructured":"Cho SW et al. 2011. Interactions between Shh Sostdc1 and Wnt signaling and a new feedback loop for spatial patterning of the teeth. Development. 138(9):1807\u20131816. https:\/\/doi.org\/10.1242\/dev.056051","DOI":"10.1242\/dev.056051"},{"key":"e_1_3_3_10_1","doi-asserted-by":"crossref","unstructured":"Dorn KV Hughes CE Rohatgi R. 2012. A smoothened-Evc2 complex transduces the Hedgehog signal at primary cilia. Dev Cell. 23(4):823\u2013835. https:\/\/doi.org\/10.1016\/j.devcel.2012.07.004","DOI":"10.1016\/j.devcel.2012.07.004"},{"key":"e_1_3_3_11_1","doi-asserted-by":"crossref","unstructured":"Elliott KH Brugmann SA. 2019. Sending mixed signals: cilia-dependent signaling during development and disease. Dev Biol. 447(1):28\u201341. https:\/\/doi.org\/10.1016\/j.ydbio.2018.03.007","DOI":"10.1016\/j.ydbio.2018.03.007"},{"key":"e_1_3_3_12_1","doi-asserted-by":"crossref","unstructured":"Galdzicka M et al. 2002. A new gene EVC2 is mutated in Ellis-van Creveld syndrome. Mol Genet Metab. 77(4):291\u2013295. https:\/\/doi.org\/10.1016\/s1096-7192(02)00178-6","DOI":"10.1016\/S1096-7192(02)00178-6"},{"key":"e_1_3_3_13_1","doi-asserted-by":"crossref","unstructured":"Garg A et al. 2020. Etv transcription factors functionally diverge from their upstream FGF signaling in lens development. Elife. 9:e51915. https:\/\/doi.org\/10.7554\/elife.51915","DOI":"10.7554\/eLife.51915"},{"key":"e_1_3_3_14_1","doi-asserted-by":"crossref","unstructured":"Hardcastle Z Rong M Hui C-C Sharpe PT. 1998. The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants. Development. 125(15):2803\u20132811. https:\/\/doi.org\/10.1242\/dev.125.15.2803","DOI":"10.1242\/dev.125.15.2803"},{"key":"e_1_3_3_15_1","doi-asserted-by":"crossref","unstructured":"Hovorakova M et al. 2020. Reawakening of ancestral dental potential as a mechanism to explain dental pathologies. Integr Comp Biol. 60(3):619\u2013629. https:\/\/doi.org\/10.1093\/icb\/icaa053","DOI":"10.1093\/icb\/icaa053"},{"key":"e_1_3_3_16_1","doi-asserted-by":"crossref","unstructured":"Hruba E et al. 2021. Loss of sprouty produces a ciliopathic skeletal phenotype in mice through upregulation of Hedgehog signaling. J Bone Miner Res. 36(11):2258\u20132274. https:\/\/doi.org\/10.1002\/jbmr.4427","DOI":"10.1002\/jbmr.4427"},{"key":"e_1_3_3_17_1","doi-asserted-by":"crossref","unstructured":"Hwang SH White KA Somatilaka BN Wang B Mukhopadhyay S. 2023. Context-dependent ciliary regulation of Hedgehog pathway repression in tissue morphogenesis. PLoS Genet. 19(11):e1011028. https:\/\/doi.org\/10.1371\/journal.pgen.1011028","DOI":"10.1371\/journal.pgen.1011028"},{"key":"e_1_3_3_18_1","doi-asserted-by":"crossref","unstructured":"Jones MR Chong L Bellusci S. 2020. Fgf10\/Fgfr2b signaling orchestrates the symphony of molecular cellular and physical processes required for harmonious airway branching morphogenesis. Front Cell Dev Biol. 8:620667. https:\/\/doi.org\/10.3389\/fcell.2020.620667","DOI":"10.3389\/fcell.2020.620667"},{"key":"e_1_3_3_19_1","doi-asserted-by":"crossref","unstructured":"Kumar V et al. 2021. The role of Notch Hedgehog and Wnt signaling pathways in the resistance of tumors to anticancer therapies. Front Cell Dev Biol. 9:650772. https:\/\/doi.org\/10.3389\/fcell.2021.650772","DOI":"10.3389\/fcell.2021.650772"},{"key":"e_1_3_3_20_1","doi-asserted-by":"crossref","unstructured":"Lohi M Tucker AS Sharpe PT. 2010. Expression of axin2 indicates a role for canonical Wnt signaling in development of the crown and root during pre- and postnatal tooth development. Dev Dyn. 239(1):160\u2013167. https:\/\/doi.org\/10.1002\/dvdy.22047","DOI":"10.1002\/dvdy.22047"},{"issue":"1","key":"e_1_3_3_21_1","first-page":"75","article-title":"Unusual pattern of inheritance and orodental changes in the Ellis-van Creveld syndrome","volume":"16","author":"Mostafa MI","year":"2005","unstructured":"Mostafa MI, Temtamy SA, el-Gammal MA, Mazen IM. 2005. Unusual pattern of inheritance and orodental changes in the Ellis-van Creveld syndrome. Genet Couns. 16(1):75\u201383.","journal-title":"Genet Couns"},{"key":"e_1_3_3_22_1","doi-asserted-by":"crossref","unstructured":"Nakatomi M. 2009. Ellis-van Creveld (EvC) syndrome: unusual oral defects in humans and Evc mutant mice. J Oral Biosci. 51(3):151\u2013157. https:\/\/doi.org\/10.1016\/S1349-0079(09)80023-6","DOI":"10.2330\/joralbiosci.51.151"},{"key":"e_1_3_3_23_1","doi-asserted-by":"crossref","unstructured":"Nakatomi M et al. 2013. Evc regulates a symmetrical response to Shh signaling in molar development. J Dent Res. 92(3):222\u2013228. https:\/\/doi.org\/10.1177\/0022034512471826","DOI":"10.1177\/0022034512471826"},{"issue":"5","key":"e_1_3_3_24_1","first-page":"501","article-title":"Ellis-van Creveld with an unusual dental anomaly: a case report","volume":"42","author":"Nethan ST","year":"2017","unstructured":"Nethan ST, Sinha S, Chandra S. 2017. Ellis-van Creveld with an unusual dental anomaly: a case report. Iran J Med Sci. 42(5):501\u2013504.","journal-title":"Iran J Med Sci"},{"key":"e_1_3_3_25_1","doi-asserted-by":"crossref","unstructured":"Palencia-Campos A et al. 2017. GLI1 inactivation is associated with developmental phenotypes overlapping with Ellis-van Creveld syndrome. Hum Mol Genet. 26(23):4556\u20134571. https:\/\/doi.org\/10.1093\/hmg\/ddx335","DOI":"10.1093\/hmg\/ddx335"},{"key":"e_1_3_3_26_1","doi-asserted-by":"crossref","unstructured":"Penon-Portmann M et al. 2022. De novo heterozygous variants in SLC30A7 are a candidate cause for Joubert syndrome. Am J Med Genet A. 188(8):2360\u20132366. https:\/\/doi.org\/10.1002\/ajmg.a.62872","DOI":"10.1002\/ajmg.a.62872"},{"key":"e_1_3_3_27_1","doi-asserted-by":"crossref","unstructured":"Popa EM Buchtova M Tucker AS. 2019. Revitalising the rudimentary replacement dentition in the mouse. Development. 146(3):dev171363. https:\/\/doi.org\/10.1242\/dev.171363","DOI":"10.1242\/dev.171363"},{"key":"e_1_3_3_28_1","doi-asserted-by":"crossref","unstructured":"Qiu T Teshima THN Hovorakova M Tucker AS. 2020. Development of the vestibular lamina in human embryos: morphogenesis and vestibule formation. Front Physiol. 11:753. https:\/\/doi.org\/10.3389\/fphys.2020.00753","DOI":"10.3389\/fphys.2020.00753"},{"key":"e_1_3_3_29_1","doi-asserted-by":"crossref","unstructured":"Qiu T et al. 2023. Molecular profiling of the vestibular lamina highlights a key role for Hedgehog signalling. Development. 150(7):dev201464. https:\/\/doi.org\/10.1242\/dev.201464","DOI":"10.1242\/dev.201464"},{"key":"e_1_3_3_30_1","doi-asserted-by":"crossref","unstructured":"Qiu T Tucker AS. 2023. Mechanisms driving vestibular lamina formation and opening in the mouse. J Anat. 242(2):224\u2013234. https:\/\/doi.org\/10.1111\/joa.13771","DOI":"10.1111\/joa.13771"},{"key":"e_1_3_3_31_1","doi-asserted-by":"crossref","unstructured":"Roubicek M Spranger J. 1984. Weyers acrodental dysostosis in a family. Clin Genet. 26(6):587\u2013590. https:\/\/doi.org\/10.1111\/j.1399-0004.1984.tb01108.x","DOI":"10.1111\/j.1399-0004.1984.tb01108.x"},{"key":"e_1_3_3_32_1","doi-asserted-by":"crossref","unstructured":"Ruiz-Perez VL et al. 2000. Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet. 24(3):283\u2013286. https:\/\/doi.org\/10.1038\/73508","DOI":"10.1038\/73508"},{"key":"e_1_3_3_33_1","doi-asserted-by":"crossref","unstructured":"Ruiz-Perez VL et al. 2007. Evc is a positive mediator of Ihh-regulated bone growth that localises at the base of chondrocyte cilia. Development. 134(16):2903\u20132912. https:\/\/doi.org\/10.1242\/dev.007542","DOI":"10.1242\/dev.007542"},{"key":"e_1_3_3_34_1","doi-asserted-by":"crossref","unstructured":"Sarkar L et al. 2000. Wnt\/Shh interactions regulate ectodermal boundary formation during mammalian tooth development. Proc Natl Acad Sci U S A. 97(9):4520\u20134524. https:\/\/doi.org\/10.1073\/pnas.97.9.4520","DOI":"10.1073\/pnas.97.9.4520"},{"key":"e_1_3_3_35_1","doi-asserted-by":"crossref","unstructured":"Sasalawad SS Hugar SM Poonacha KS Mallikarjuna R. 2013. Ellis-van Creveld syndrome. BMJ Case Rep. 2013:bcr2013009463. https:\/\/doi.org\/10.1136\/bcr-2013-009463","DOI":"10.1136\/bcr-2013-009463"},{"key":"e_1_3_3_36_1","doi-asserted-by":"crossref","unstructured":"Seppala M et al. 2007. Gas1 is a modifier for holoprosencephaly and genetically interacts with Sonic Hedgehog. J Clin Invest. 117(6):1575\u20131584. https:\/\/doi.org\/10.1172\/jci32032","DOI":"10.1172\/JCI32032"},{"key":"e_1_3_3_37_1","doi-asserted-by":"crossref","unstructured":"Ulucan H et al. 2008. Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene. BMC Med Genet. 9:92. https:\/\/doi.org\/10.1186\/1471-2350-9-92","DOI":"10.1186\/1471-2350-9-92"},{"key":"e_1_3_3_38_1","doi-asserted-by":"crossref","unstructured":"Zhang H et al. 2015. Generation of Evc2\/Limbin global and conditional KO mice and its roles during mineralized tissue formation. Genesis. 53(9):612\u2013626. https:\/\/doi.org\/10.1002\/dvg.22879","DOI":"10.1002\/dvg.22879"},{"key":"e_1_3_3_39_1","doi-asserted-by":"crossref","unstructured":"Zhang H et al. 2017. Loss of function of Evc2 in dental mesenchyme leads to hypomorphic enamel. J Dent Res. 96(4):421\u2013429. https:\/\/doi.org\/10.1177\/0022034516683674","DOI":"10.1177\/0022034516683674"},{"key":"e_1_3_3_40_1","doi-asserted-by":"crossref","unstructured":"Zhang H et al. 2022. Elevated WNT signaling and compromised Hedgehog signaling due to Evc2 loss of function contribute to the abnormal molar patterning. Front Dent Med. 3:876015. https:\/\/doi.org\/10.3389\/fdmed.2022.876015","DOI":"10.3389\/fdmed.2022.876015"}],"container-title":["Journal of Dental Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/00220345261430674","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/00220345261430674","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/00220345261430674","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T20:55:11Z","timestamp":1793566511000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/00220345261430674"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,30]]},"references-count":39,"alternative-id":["10.1177\/00220345261430674"],"URL":"https:\/\/doi.org\/10.1177\/00220345261430674","relation":{},"ISSN":["0022-0345","1544-0591"],"issn-type":[{"value":"0022-0345","type":"print"},{"value":"1544-0591","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,30]]},"article-number":"00220345261430674"}}