{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:49:04Z","timestamp":1760240944099,"version":"build-2065373602"},"reference-count":38,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,10,23]],"date-time":"2019-10-23T00:00:00Z","timestamp":1571788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001722","name":"Koninklijke Nederlandse Akademie van Wetenschappen","doi-asserted-by":"publisher","award":["05CDP035"],"award-info":[{"award-number":["05CDP035"]}],"id":[{"id":"10.13039\/501100001722","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Orofacial clefts (OFCs) are the most frequent craniofacial birth defects. An orofacial cleft (OFC) occurs as a result of deviations in palatogenesis. Cell proliferation, differentiation, adhesion, migration and apoptosis are crucial in palatogenesis. We hypothesized that deregulation of these processes in oral keratinocytes contributes to OFC. We performed microarray expression analysis on palatal keratinocytes from OFC and non-OFC individuals. Principal component analysis showed a clear difference in gene expression with 24% and 17% for the first and second component, respectively. In OFC cells, 228 genes were differentially expressed (p &lt; 0.001). Gene ontology analysis showed enrichment of genes involved in \u03b21 integrin-mediated adhesion and migration, as well as in P-cadherin expression. A scratch assay demonstrated reduced migration of OFC keratinocytes (343.6 \u00b1 29.62 \u03bcm) vs. non-OFC keratinocytes (503.4 \u00b1 41.81 \u03bcm, p &lt; 0.05). Our results indicate that adhesion and migration are deregulated in OFC keratinocytes, which might contribute to OFC pathogenesis.<\/jats:p>","DOI":"10.3390\/genes10110836","type":"journal-article","created":{"date-parts":[[2019,10,25]],"date-time":"2019-10-25T03:20:36Z","timestamp":1571973636000},"page":"836","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Deregulated Adhesion Program in Palatal Keratinocytes of Orofacial Cleft Patients"],"prefix":"10.3390","volume":"10","author":[{"given":"Aysel","family":"Mammadova","sequence":"first","affiliation":[{"name":"Department of Dentistry, Section Orthodontics and Craniofacial Biology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carine E.L.","family":"Carels","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium"},{"name":"Department of Oral Health Sciences, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Zhou","sequence":"additional","affiliation":[{"name":"The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, Wuhan University, Wuhan 430079, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Gilissen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria P.A.C.","family":"Helmich","sequence":"additional","affiliation":[{"name":"Department of Dentistry, Section Orthodontics and Craniofacial Biology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuan","family":"Bian","sequence":"additional","affiliation":[{"name":"The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, Wuhan University, Wuhan 430079, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2434-3986","authenticated-orcid":false,"given":"Huiqing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands"},{"name":"Department of Molecular Developmental Biology, Radboud Institute for Molecular Life Sciences (RIMLS), P.O. Box 9101, 6500 HB Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1616-1576","authenticated-orcid":false,"given":"Johannes W.","family":"Von den Hoff","sequence":"additional","affiliation":[{"name":"Department of Dentistry, Section Orthodontics and Craniofacial Biology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"511e","DOI":"10.1097\/PRS.0b013e3182402dd1","article-title":"Updating the epidemiology of cleft lip with or without cleft palate","volume":"129","author":"Tanaka","year":"2012","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nrg2933","article-title":"Cleft lip and palate: Understanding genetic and environmental influences","volume":"12","author":"Dixon","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/bs.ctdb.2015.07.002","article-title":"Cellular and molecular mechanisms of palatogenesis","volume":"115","author":"Lan","year":"2015","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.1002\/dvdy.20833","article-title":"Recent advances in craniofacial morphogenesis","volume":"235","author":"Chai","year":"2006","journal-title":"Dev. Dyn."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3891","DOI":"10.1172\/JCI71946","article-title":"Periderm prevents pathological epithelial adhesions during embryogenesis","volume":"124","author":"Richardson","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1002\/jcp.24856","article-title":"TGFbeta3 regulates periderm removal through DeltaNp63 in the developing palate","volume":"230","author":"Hu","year":"2015","journal-title":"J. Cell. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1111\/j.1365-2443.2012.01601.x","article-title":"Periderm cells covering palatal shelves have tight junctions and their desquamation reduces the polarity of palatal shelf epithelial cells in palatogenesis","volume":"17","author":"Yoshida","year":"2012","journal-title":"Genes Cells Devoted Mol. Cell. Mech."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1242\/dev.00907","article-title":"Death is the major fate of medial edge epithelial cells and the cause of basal lamina degradation during palatogenesis","volume":"131","author":"Cuervo","year":"2004","journal-title":"Development"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.ydbio.2005.07.027","article-title":"Fate-mapping of the epithelial seam during palatal fusion rules out epithelial-mesenchymal transformation","volume":"285","author":"Hallberg","year":"2005","journal-title":"Dev. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kim, S., Lewis, A.E., Singh, V., Ma, X., Adelstein, R., and Bush, J.O. (2015). Convergence and extrusion are required for normal fusion of the mammalian secondary palate. PLoS Biol., 13.","DOI":"10.1371\/journal.pbio.1002122"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/385537a0","article-title":"Integrin-ligand binding properties govern cell migration speed through cell-substratum adhesiveness","volume":"385","author":"Palecek","year":"1997","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1177\/00220345990780120401","article-title":"TGFbeta isoforms and decorin gene expression are modified in fibroblasts obtained from non-syndromic cleft lip and palate subjects","volume":"78","author":"Bodo","year":"1999","journal-title":"J. Dent. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"237","DOI":"10.2119\/2006-00026.Baroni","article-title":"Retinoic acid, GABA-ergic, and TGF-beta signaling systems are involved in human cleft palate fibroblast phenotype","volume":"12","author":"Baroni","year":"2006","journal-title":"Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1177\/00220345980770080901","article-title":"Diphenyihydantoin affects glycosaminoglycans and collagen production by human fibroblasts from cleft palate patients","volume":"77","author":"Bosi","year":"1998","journal-title":"J. Dent. Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Beyeler, J., Schnyder, I., Katsaros, C., and Chiquet, M. (2014). Accelerated wound closure in vitro by fibroblasts from a subgroup of cleft lip\/palate patients: Role of transforming growth factor-alpha. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0111752"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1177\/154405910808700806","article-title":"Cleft Palate Cells Can Regenerate a Palatal Mucosa In Vitro","volume":"87","author":"Liu","year":"2008","journal-title":"J. Dent. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1089\/scd.2009.0288","article-title":"Functional differences between mesenchymal stem cell populations are reflected by their transcriptome","volume":"19","author":"Jansen","year":"2010","journal-title":"Stem Cells Dev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/nar\/gkn923","article-title":"Bioinformatics enrichment tools: Paths toward the comprehensive functional analysis of large gene lists","volume":"37","author":"Huang","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","author":"Sherman","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1111\/j.0022-202X.2005.23935.x","article-title":"High expression levels of keratinocyte antimicrobial proteins in psoriasis compared with atopic dermatitis","volume":"125","author":"Zeeuwen","year":"2005","journal-title":"J. Investig. Dermatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nbt1203","article-title":"Gene prioritization through genomic data fusion","volume":"24","author":"Aerts","year":"2006","journal-title":"Nat. Biotechnol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"W377","DOI":"10.1093\/nar\/gkn325","article-title":"ENDEAVOUR update: A web resource for gene prioritization in multiple species","volume":"36","author":"Tranchevent","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s00441-016-2446-2","article-title":"Integrin-mediated regulation of epidermal wound functions","volume":"365","author":"DiPersio","year":"2016","journal-title":"Cell Tissue Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1242\/dev.129.9.2303","article-title":"A crucial role of \u03b21 integrins for keratinocyte migration in vitro and during cutaneous wound repair","volume":"129","author":"Grose","year":"2002","journal-title":"Development"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/sj.jid.5700505","article-title":"Integrin alpha3beta1-dependent activation of FAK\/Src regulates Rac1-mediated keratinocyte polarization on laminin-5","volume":"127","author":"Choma","year":"2007","journal-title":"J. Investig. Dermatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/nature01148","article-title":"Rho GTPases in cell biology","volume":"420","year":"2002","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"135","DOI":"10.4161\/cam.22418","article-title":"Laminin 332 in junctional epidermolysis bullosa","volume":"7","author":"Kiritsi","year":"2013","journal-title":"Cell Adhes. Migr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1242\/jcs.113.2.259","article-title":"Altered synthesis of laminin 1 and absence of basement membrane component deposition in \u03b21 integrin-deficient embryoid bodies","volume":"113","author":"Aumailley","year":"2000","journal-title":"J. Cell Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1177\/002215540004800712","article-title":"Immunolocalization of tenascin-c, a9 integrin subunit, and avb6 integrin during wound healing in human oral mucosa","volume":"48","author":"Hildebrand","year":"2000","journal-title":"J. Histochem. Cytochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.matbio.2012.01.006","article-title":"Thrombospondin1 in tissue repair and fibrosis: TGF-beta-dependent and independent mechanisms","volume":"31","author":"Sweetwyne","year":"2012","journal-title":"Matrix Biol. J. Int. Soc. Matrix Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1083\/jcb.201505105","article-title":"P-cadherin promotes collective cell migration via a Cdc42-mediated increase in mechanical forces","volume":"212","author":"Plutoni","year":"2016","journal-title":"J. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/ncb3135","article-title":"Control of cell-cell forces and collective cell dynamics by the intercellular adhesome","volume":"17","author":"Bazellieres","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1083\/jcb.201207148","article-title":"Substrate stiffness regulates cadherin-dependent collective migration through myosin-II contractility","volume":"199","author":"Ng","year":"2012","journal-title":"J. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e27363","DOI":"10.4161\/jkst.27363","article-title":"Engaged for survival: From cadherin ligation to STAT3 activation","volume":"2","author":"Geletu","year":"2013","journal-title":"Jak-Stat"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1126\/science.1092053","article-title":"Cell migration: Integrating signals from front to back","volume":"302","author":"Ridley","year":"2003","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.ccr.2011.06.018","article-title":"ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma","volume":"20","author":"Gaggioli","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1083\/jcb.146.5.1117","article-title":"Afadin: A key molecule essential for structural organization of cell\u2013cell junctions of polarized epithelia during embryogenesis","volume":"146","author":"Ikeda","year":"1999","journal-title":"J. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/78119","article-title":"Mutations of PVRL1, encoding a cell-cell adhesion molecule\/herpesvirus receptor, in cleft lip\/palateectodermal dysplasia","volume":"25","author":"Suzuki","year":"2000","journal-title":"Nat. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/10\/11\/836\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:28:43Z","timestamp":1760189323000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/10\/11\/836"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,23]]},"references-count":38,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["genes10110836"],"URL":"https:\/\/doi.org\/10.3390\/genes10110836","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2019,10,23]]}}}