{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:43:44Z","timestamp":1792172624229,"version":"4.4.0"},"reference-count":85,"publisher":"Portland Press Ltd.","issue":"1","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,11,15]]},"abstract":"<jats:p>Oculodentodigital dysplasia (ODDD) is primarily an autosomal dominant disorder linked to over 70 GJA1 gene [connexin43 (Cx43)] mutations. For nearly a decade, our laboratory has been investigating the relationship between Cx43 and ODDD by expressing disease-linked mutants in reference cells, tissue-relevant cell lines, 3D organ cultures and by using genetically modified mouse models of human disease. Although salient features of Cx43 mutants have been revealed, these models do not necessarily reflect the complexity of the human context. To further overcome these limitations, we have acquired dermal fibroblasts from two ODDD-affected individuals harbouring D3N and V216L mutations in Cx43, along with familial controls. Using these ODDD patient dermal fibroblasts, which naturally produce less GJA1 gene product, along with RNAi and RNA activation (RNAa) approaches, we show that manipulating Cx43 expression triggers cellular gene reprogramming. Quantitative RT-PCR, Western blot and immunofluorescent analysis of ODDD patient fibroblasts show unusually high levels of extracellular matrix (ECM)-interacting proteins, including integrin \u03b15\u03b21, matrix metalloproteinases as well as secreted ECM proteins collagen-I and laminin. Cx43 knockdown in familial control cells produces similar effects on ECM expression, whereas Cx43 transcriptional up-regulation using RNAa decreases production of collagen-I. Interestingly, the enhanced levels of ECM-associated proteins in ODDD V216L fibroblasts is not only a consequence of increased ECM gene expression, but also due to an apparent deficit in collagen-I secretion which may further contribute to impaired collagen gel contraction in ODDD fibroblasts. These findings further illuminate the altered function of Cx43\u00a0in ODDD-affected individuals and highlight the impact of manipulating Cx43 expression in human cells.<\/jats:p>","DOI":"10.1042\/bj20150652","type":"journal-article","created":{"date-parts":[[2015,9,9]],"date-time":"2015-09-09T02:03:37Z","timestamp":1441764217000},"page":"55-69","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Manipulating Cx43 expression triggers gene reprogramming events in dermal fibroblasts from oculodentodigital dysplasia patients"],"prefix":"10.1042","volume":"472","author":[{"given":"Jessica\u00a0L.","family":"Esseltine","sequence":"first","affiliation":[{"name":"Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada, N6A-5C1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada, N6A-5C1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada, N6A-5C1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John\u00a0J.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada, N6A-5C1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacinda","family":"Sampson","sequence":"additional","affiliation":[{"name":"Department of Neurology, Stanford University Medical Center, Palo Alto, CA 94305, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dale\u00a0W.","family":"Laird","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada, N6A-5C1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2015,10,30]]},"reference":[{"key":"2021112216253417100_B1","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.2174\/0929867033456927","article-title":"Transfer of biologically important molecules between cells through gap junction channels","volume":"10","author":"Alexander","year":"2003","journal-title":"Curr. 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