{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:45:15Z","timestamp":1792035915361,"version":"4.4.0"},"reference-count":42,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2016,9,19]],"date-time":"2016-09-19T00:00:00Z","timestamp":1474243200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,9,19]],"date-time":"2016-09-19T00:00:00Z","timestamp":1474243200000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,9,19]],"date-time":"2016-09-19T00:00:00Z","timestamp":1474243200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003329","name":"Ministerio de Econom\u00eda y Competitividad","doi-asserted-by":"publisher","award":["BFU2014-52299-P"],"award-info":[{"award-number":["BFU2014-52299-P"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["ISCIII-RD12\/0019-0022 (ISCIII-TERCEL)"],"award-info":[{"award-number":["ISCIII-RD12\/0019-0022 (ISCIII-TERCEL)"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002878","name":"Consejer\u00eda de Econom\u00eda, Innovaci\u00f3n, Ciencia y Empleo, Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["P11-CTS-07564"],"award-info":[{"award-number":["P11-CTS-07564"]}],"id":[{"id":"10.13039\/501100002878","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI14-00804"],"award-info":[{"award-number":["PI14-00804"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    Congenital diaphragmatic hernia (CDH) is a severe birth defect. Wt1-null mouse embryos develop CDH but the mechanisms regulated by WT1 are unknown. We have generated a murine model with conditional deletion of WT1 in the lateral plate mesoderm, using the G2 enhancer of the\n                    <jats:italic>Gata4<\/jats:italic>\n                    gene as a driver. 80% of G2-\n                    <jats:italic>Gata4<\/jats:italic>\n                    <jats:sup>Cre<\/jats:sup>\n                    ;\n                    <jats:italic>Wt1<\/jats:italic>\n                    <jats:sup>fl\/fl<\/jats:sup>\n                    embryos developed typical Bochdalek-type CDH. We show that the posthepatic mesenchymal plate coelomic epithelium gives rise to a mesenchyme that populates the pleuroperitoneal folds isolating the pleural cavities before the migration of the somitic myoblasts. This process fails when Wt1 is deleted from this area. Mutant embryos show Raldh2 downregulation in the lateral mesoderm, but not in the intermediate mesoderm. The mutant phenotype was partially rescued by retinoic acid treatment of the pregnant females. Replacement of intermediate by lateral mesoderm recapitulates the evolutionary origin of the diaphragm in mammals. CDH might thus be viewed as an evolutionary atavism.\n                  <\/jats:p>","DOI":"10.7554\/elife.16009","type":"journal-article","created":{"date-parts":[[2016,9,19]],"date-time":"2016-09-19T12:00:24Z","timestamp":1474286424000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.16009","source":"Crossref","is-referenced-by-count":48,"title":["Conditional deletion of WT1 in the septum transversum mesenchyme causes congenital diaphragmatic hernia in mice"],"prefix":"10.7554","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9686-473X","authenticated-orcid":true,"given":"Rita","family":"Carmona","sequence":"first","affiliation":[{"name":"Department of Animal Biology, University of M\u00e1laga, M\u00e1laga, Spain"},{"name":"Andalusian Center for Nanomedicine and Biotechnology (BIONAND), M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Ca\u00f1ete","sequence":"additional","affiliation":[{"name":"Department of Animal Biology, University of M\u00e1laga, M\u00e1laga, Spain"},{"name":"Andalusian Center for Nanomedicine and Biotechnology (BIONAND), M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Cano","sequence":"additional","affiliation":[{"name":"Max Delbru\u0308ck Center for Molecular Medicine, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Ariza","sequence":"additional","affiliation":[{"name":"Department of Animal Biology, University of M\u00e1laga, M\u00e1laga, Spain"},{"name":"Andalusian Center for Nanomedicine and Biotechnology (BIONAND), M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anabel","family":"Rojas","sequence":"additional","affiliation":[{"name":"Andalusian Center of Molecular Biology and Regenerative Medicine (CABIMER), Sevilla, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM), Sevilla, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6392-6802","authenticated-orcid":true,"given":"Ramon","family":"Mu\u00f1oz-Ch\u00e1puli","sequence":"additional","affiliation":[{"name":"Department of Animal Biology, University of M\u00e1laga, M\u00e1laga, Spain"},{"name":"Andalusian Center for Nanomedicine and Biotechnology (BIONAND), M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2016,9,19]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1002\/ajmg.a.32168","article-title":"Denys-Drash syndrome and congenital diaphragmatic hernia: another case with the 1097G > A(Arg366His) mutation","volume":"146A","author":"Antonius","year":"2008","journal-title":"American Journal of Medical Genetics Part A"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1002\/dvdy.24373","article-title":"Coelomic epithelium-derived cells in visceral morphogenesis","volume":"245","author":"Ariza","year":"2016","journal-title":"Developmental Dynamics"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"L1310","DOI":"10.1152\/ajplung.00257.2002","article-title":"Diaphragm defects occur in a CDH hernia model independently of myogenesis and lung formation","volume":"283","author":"Babiuk","year":"2002","journal-title":"American Journal of Physiology - Lung Cellular and Molecular Physiology"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1002\/cne.10503","article-title":"Embryological origins and development of the rat diaphragm","volume":"455","author":"Babiuk","year":"2003","journal-title":"Journal of Comparative Neurology"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"L322","DOI":"10.1152\/ajplung.00424.2012","article-title":"Wt1-expressing progenitors contribute to multiple tissues in the developing lung","volume":"305","author":"Cano","year":"2013","journal-title":"AJP:\u00a0Lung Cellular and Molecular Physiology"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1073\/pnas.1509834113","article-title":"Extracardiac septum transversum\/proepicardial endothelial cells pattern embryonic coronary arterio-venous connections","volume":"113","author":"Cano","year":"2016","journal-title":"PNAS"},{"key":"bib7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0055890","article-title":"Cells derived from the coelomic epithelium contribute to multiple gastrointestinal tissues in mouse embryos","volume":"8","author":"Carmona","year":"2013","journal-title":"PLoS One"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1002\/dvg.22353","article-title":"Epithelial-to-mesenchymal transition in epicardium is independent of Snail1","volume":"51","author":"Casanova","year":"2013","journal-title":"Genesis"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1053\/j.sempedsurg.2007.01.004","article-title":"Diaphragm development and congenital diaphragmatic hernia","volume":"16","author":"Clugston","year":"2007","journal-title":"Seminars in Pediatric Surgery"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.2353\/ajpath.2006.060445","article-title":"Teratogen-induced, dietary and genetic models of congenital diaphragmatic hernia share a common mechanism of pathogenesis","volume":"169","author":"Clugston","year":"2006","journal-title":"American Journal of Pathology"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1002\/bdra.20613","article-title":"Early development of the primordial mammalian diaphragm and cellular mechanisms of nitrofen-induced congenital diaphragmatic hernia","volume":"88","author":"Clugston","year":"2010","journal-title":"Birth Defects Research Part A, Clinical and Molecular Teratology"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1161\/CIRCRESAHA.110.229062","article-title":"Differential Notch signaling in the epicardium is required for cardiac inflow development and coronary vessel morphogenesis","volume":"108","author":"del Monte","year":"2011","journal-title":"Circulation Research"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"2358","DOI":"10.1002\/hep.27005","article-title":"GATA4 loss in the septum transversum mesenchyme promotes liver fibrosis in mice","volume":"59","author":"Delgado","year":"2014","journal-title":"Hepatology"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1002\/bdrb.21037","article-title":"Decreased expression of GATA4 in the diaphragm of nitrofen-induced congenital diaphragmatic hernia","volume":"98","author":"Dingemann","year":"2013","journal-title":"Birth Defects Research Part B: Developmental and Reproductive Toxicology"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1007\/s00383-010-2795-y","article-title":"Expression of the Wilm's tumor gene WT1 during diaphragmatic development in the nitrofen model for congenital diaphragmatic hernia","volume":"27","author":"Dingemann","year":"2011","journal-title":"Pediatric Surgery International"},{"key":"bib16","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1242\/dev.109.4.787","article-title":"Pax2, a new murine paired-box-containing gene and its expression in the developing excretory system","volume":"109","author":"Dressler","year":"1990","journal-title":"Development"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1016\/j.devcel.2011.07.014","article-title":"A wt1-controlled chromatin switching mechanism underpins tissue-specific wnt4 activation and repression","volume":"21","author":"Essafi","year":"2011","journal-title":"Developmental Cell"},{"key":"bib18","doi-asserted-by":"crossref","DOI":"10.5962\/bhl.title.82144","volume-title":"Studies on the Structure and Development of Vertebrates","author":"Goodrich","year":"1930"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1002\/dvdy.20685","article-title":"In vivo and in vitro analysis of the vasculogenic potential of avian proepicardial and epicardial cells","volume":"235","author":"Guadix","year":"2006","journal-title":"Developmental Dynamics"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1002\/ar.21351","article-title":"Pleuroperitoneal canal closure and the fetal adrenal gland","volume":"294","author":"Hayashi","year":"2011","journal-title":"The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/j.ydbio.2007.09.014","article-title":"Wt1 and retinoic acid signaling are essential for stellate cell development and liver morphogenesis","volume":"312","author":"Ijpenberg","year":"2007","journal-title":"Developmental Biology"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1007\/BF00303142","article-title":"Experimental study on embryogenesis of congenital diaphragmatic hernia","volume":"169","author":"Iritani","year":"1984","journal-title":"Anatomy and Embryology"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"1580","DOI":"10.1002\/ajmg.a.31321","article-title":"Congenital diaphragmatic hernia associated with duplication of 11q23-qter","volume":"140","author":"Klaassens","year":"2006","journal-title":"American Journal of Medical Genetics Part A"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1016\/0092-8674(93)90515-R","article-title":"WT-1 is required for early kidney development","volume":"74","author":"Kreidberg","year":"1993","journal-title":"Cell"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"8499","DOI":"10.1073\/pnas.0803578105","article-title":"The direction of gut looping is established by changes in the extracellular matrix and in cell:cell adhesion","volume":"105","author":"Kurpios","year":"2008","journal-title":"PNAS"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/ng.494","article-title":"Wt1 is required for cardiovascular progenitor cell formation through transcriptional control of Snail and E-cadherin","volume":"42","author":"Mart\u00ednez-Estrada","year":"2010","journal-title":"Nature Genetics"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1053\/j.sempedsurg.2011.03.006","article-title":"The embryology of the diaphragm","volume":"20","author":"Mayer","year":"2011","journal-title":"Seminars in Pediatric Surgery"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1038\/ng.3250","article-title":"Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias","volume":"47","author":"Merrell","year":"2015","journal-title":"Nature Genetics"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1007\/s00383-008-2140-x","article-title":"Congenital diaphragmatic hernia and retinoids: searching for an etiology","volume":"24","author":"Montedonico","year":"2008","journal-title":"Pediatric Surgery International"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/S0925-4773(98)00188-9","article-title":"YAC transgenic analysis reveals Wilms' tumour 1 gene activity in the proliferating coelomic epithelium, developing diaphragm and limb","volume":"79","author":"Moore","year":"1998","journal-title":"Mechanisms of Development"},{"key":"bib31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0045100","article-title":"Partial absence of pleuropericardial membranes in Tbx18- and Wt1-deficient mice","volume":"7","author":"Norden","year":"2012","journal-title":"PLoS One"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1161\/CIRCRESAHA.110.217455","article-title":"Wt1 and retinoic acid signaling in the subcoelomic mesenchyme control the development of the pleuropericardial membranes and the sinus horns","volume":"106","author":"Norden","year":"2010","journal-title":"Circulation Research"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.ydbio.2015.08.009","article-title":"Wt1 and \u03b2-catenin cooperatively regulate diaphragm development in the mouse","volume":"407","author":"Paris","year":"2015","journal-title":"Developmental Biology"},{"key":"bib34","first-page":"1993","volume-title":"GeneReviews\u00ae[Internet]","author":"Pober","year":"2010"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"1995","DOI":"10.1242\/dev.035592","article-title":"Interplay between activin and Hox genes determines the formation of the kidney morphogenetic field","volume":"136","author":"Preger-Ben Noon","year":"2009","journal-title":"Development"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"3405","DOI":"10.1242\/dev.01913","article-title":"Gata4 expression in lateral mesoderm is downstream of BMP4 and is activated directly by Forkhead and GATA transcription factors through a distal enhancer element","volume":"132","author":"Rojas","year":"2005","journal-title":"Development"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1002\/ajmg.a.30654","article-title":"Congenital diaphragmatic hernia in WAGR syndrome","volume":"134","author":"Scott","year":"2005","journal-title":"American Journal of Medical Genetics Part A"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/j.jpedsurg.2007.10.050","article-title":"Prenatal treatment with retinoic acid accelerates type 1 alveolar cell proliferation of the hypoplastic lung in the nitrofen model of congenital diaphragmatic hernia","volume":"43","author":"Sugimoto","year":"2008","journal-title":"Journal of Pediatric Surgery"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"2312","DOI":"10.1002\/ajmg.a.31924","article-title":"WT1 mutations in Meacham syndrome suggest a coelomic mesothelial origin of the cardiac and diaphragmatic malformations","volume":"143A","author":"Suri","year":"2007","journal-title":"American Journal of Medical Genetics Part A"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1002\/bdra.20481","article-title":"Unique spatial and cellular expression patterns of Hoxa5, Hoxb4, and Hoxb6 proteins in normal developing murine lung are modified in pulmonary hypoplasia","volume":"82","author":"Volpe","year":"2008","journal-title":"Birth Defects Research Part A"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/j.ydbio.2011.05.668","article-title":"WT1 regulates epicardial epithelial to mesenchymal transition through \u03b2-catenin and retinoic acid signaling pathways","volume":"356","author":"von Gise","year":"2011","journal-title":"Developmental Biology"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.ydbio.2012.04.020","article-title":"Epicardially derived fibroblasts preferentially contribute to the parietal leaflets of the atrioventricular valves in the murine heart","volume":"366","author":"Wessels","year":"2012","journal-title":"Developmental Biology"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/16009\/elife-16009-v1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/16009\/elife-16009-v1.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/16009","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T20:52:04Z","timestamp":1697057524000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/16009"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,9,19]]},"references-count":42,"alternative-id":["10.7554\/eLife.16009"],"URL":"https:\/\/doi.org\/10.7554\/elife.16009","archive":["CLOCKSS"],"relation":{"has-review":[{"id-type":"doi","id":"10.7554\/eLife.16009.012","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.16009.013","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,9,19]]},"article-number":"e16009"}}