{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T20:38:41Z","timestamp":1772138321093,"version":"3.50.1"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"13","license":[{"start":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T00:00:00Z","timestamp":1680220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HD098458"],"award-info":[{"award-number":["HD098458"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["OD016167"],"award-info":[{"award-number":["OD016167"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["OD023469"],"award-info":[{"award-number":["OD023469"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Molecular and Human Genetics Functional Genomics Core at Baylor College of Medicine"},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007857","name":"Intellectual and Developmental Disabilities Research Center","doi-asserted-by":"publisher","award":["HD083092"],"award-info":[{"award-number":["HD083092"]}],"id":[{"id":"10.13039\/100007857","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hybridization Core at Baylor College of Medicine"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>SOX7 is a transcription factor-encoding gene located in a region on chromosome 8p23.1 that is recurrently deleted in individuals with ventricular septal defects (VSDs). We have previously shown that Sox7\u2212\/\u2212 embryos die of heart failure around E11.5. Here, we demonstrate that these embryos have hypocellular endocardial cushions with severely reduced numbers of mesenchymal cells. Ablation of Sox7 in the endocardium also resulted in hypocellular endocardial cushions, and we observed VSDs in rare E15.5 Sox7flox\/\u2212;Tie2-Cre and Sox7flox\/flox;Tie2-Cre embryos that survived to E15.5. In atrioventricular explant studies, we showed that SOX7 deficiency leads to a severe reduction in endocardial-to-mesenchymal transition (EndMT). RNA-seq studies performed on E9.5 Sox7\u2212\/\u2212 heart tubes revealed severely reduced Wnt4 transcript levels. Wnt4 is expressed in the endocardium and promotes EndMT by acting in a paracrine manner to increase the expression of Bmp2 in the myocardium. Both WNT4 and BMP2 have been previously implicated in the development of VSDs in individuals with 46,XX sex reversal with dysgenesis of kidney, adrenals and lungs (SERKAL) syndrome and in individuals with short stature, facial dysmorphism and skeletal anomalies with or without cardiac anomalies 1 (SSFSC1) syndrome, respectively. We now show that Sox7 and Wnt4 interact genetically in the development of VSDs through their additive effects on endocardial cushion development with Sox7+\/\u2212;Wnt4+\/\u2212 double heterozygous embryos having hypocellular endocardial cushions and perimembranous and muscular VSDs not seen in their Sox7+\/\u2212 and Wnt4+\/\u2212 littermates. These results provide additional evidence that SOX7, WNT4 and BMP2 function in the same pathway during mammalian septal development and that their deficiency can contribute to the development of VSDs in humans.<\/jats:p>","DOI":"10.1093\/hmg\/ddad050","type":"journal-article","created":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T10:01:31Z","timestamp":1680256891000},"page":"2152-2161","source":"Crossref","is-referenced-by-count":2,"title":["SOX7 deficiency causes ventricular septal defects through its effects on endocardial-to-mesenchymal transition and the expression of\n                    <i>Wnt4<\/i>\n                    and\n                    <i>Bmp2<\/i>"],"prefix":"10.1093","volume":"32","author":[{"given":"Andr\u00e9s","family":"Hern\u00e1ndez-Garc\u00eda","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine E","family":"Pendleton","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sangbae","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yumei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bum J","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hitisha P","family":"Zaveri","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerie K","family":"Jordan","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aliska M","family":"Berry","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M Cecilia","family":"Ljungberg","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rainer B","family":"Lanz","sequence":"additional","affiliation":[{"name":"Department of Molecular & Cellular Biology, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Quantitative and Computational Biosciences, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daryl A","family":"Scott","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Department of Molecular Physiology and Biophysics, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,3,31]]},"reference":[{"key":"2023062021505130900_ref1","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1002\/ajmg.a.32896","article-title":"Chromosome 8p23.1 deletions as a cause of complex congenital heart defects and diaphragmatic hernia","volume":"149A","author":"Wat","year":"2009","journal-title":"Am. J. Med. Genet. A"},{"key":"2023062021505130900_ref2","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1086\/302330","article-title":"Delineation of the critical deletion region for congenital heart defects, on chromosome 8p23.1","volume":"64","author":"Devriendt","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"2023062021505130900_ref3","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1002\/ajmg.a.30778","article-title":"Molecular characterization of del(8)(p23.1p23.1) in a case of congenital diaphragmatic hernia","volume":"136","author":"Shimokawa","year":"2005","journal-title":"Am. J. Med. Genet. A"},{"key":"2023062021505130900_ref4","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1002\/pd.1468","article-title":"Prenatal diagnosis of de novo deletions of 8p23.1 or 15q26.1 in two fetuses with diaphragmatic hernia and congenital heart defects","volume":"26","author":"Lopez","year":"2006","journal-title":"Prenat. Diagn."},{"key":"2023062021505130900_ref5","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1136\/jmg.2004.028787","article-title":"Fryns syndrome phenotype caused by chromosome microdeletions at 15q26.2 and 8p23.1","volume":"42","author":"Slavotinek","year":"2005","journal-title":"J. Med. Genet."},{"key":"2023062021505130900_ref6","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/nature01827","article-title":"GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5","volume":"424","author":"Garg","year":"2003","journal-title":"Nature"},{"key":"2023062021505130900_ref7","doi-asserted-by":"crossref","first-page":"e97","DOI":"10.1136\/jmg.2004.018895","article-title":"A novel GATA4 mutation completely segregated with atrial septal defect in a large Japanese family","volume":"41","author":"Okubo","year":"2004","journal-title":"J. Med. Genet."},{"key":"2023062021505130900_ref8","first-page":"1672","article-title":"SOX7 loss-of-function variation as a cause of familial congenital heart disease","volume":"14","author":"Huang","year":"2022","journal-title":"Am. J. Transl. Res."},{"key":"2023062021505130900_ref9","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1002\/dvdy.20565","article-title":"SOX7 and SOX18 are essential for cardiogenesis in Xenopus","volume":"234","author":"Zhang","year":"2005","journal-title":"Dev. Dyn."},{"key":"2023062021505130900_ref10","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.ydbio.2008.01.028","article-title":"Zebrafish Sox7 and Sox18 function together to control arterial-venous identity","volume":"317","author":"Pendeville","year":"2008","journal-title":"Dev. 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Genet."},{"key":"2023062021505130900_ref13","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/s41419-021-03658-z","article-title":"The transcription factor Sox7 modulates endocardiac cushion formation contributed to atrioventricular septal defect through Wnt4\/Bmp2 signaling","volume":"12","author":"Hong","year":"2021","journal-title":"Cell Death Dis."},{"key":"2023062021505130900_ref14","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1006\/dbio.2000.0106","article-title":"Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo","volume":"230","author":"Kisanuki","year":"2001","journal-title":"Dev. 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J. Med. Genet."},{"key":"2023062021505130900_ref26","doi-asserted-by":"crossref","first-page":"e32","DOI":"10.1136\/jmg.2004.025395","article-title":"GATA4 zinc finger mutations as a molecular rationale for septation defects of the human heart","volume":"42","author":"Reamon-Buettner","year":"2005","journal-title":"J. Med. Genet."},{"key":"2023062021505130900_ref27","doi-asserted-by":"crossref","first-page":"e16","DOI":"10.1136\/jmg.2004.026740","article-title":"Spectrum of atrial septal defects associated with mutations of NKX2.5 and GATA4 transcription factors","volume":"42","author":"Sarkozy","year":"2005","journal-title":"J. Med. Genet."},{"key":"2023062021505130900_ref28","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1016\/j.athoracsur.2008.02.027","article-title":"Endothelial expression of bone morphogenetic protein receptor type 1a is required for atrioventricular valve formation","volume":"85","author":"Kaneko","year":"2008","journal-title":"Ann. Thorac. Surg."},{"key":"2023062021505130900_ref29","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/j.ydbio.2006.03.043","article-title":"Bmp2 instructs cardiac progenitors to form the heart-valve-inducing field","volume":"295","author":"Rivera-Feliciano","year":"2006","journal-title":"Dev. Biol."},{"key":"2023062021505130900_ref30","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1161\/CIRCRESAHA.109.201566","article-title":"Heart valve development: regulatory networks in development and disease","volume":"105","author":"Combs","year":"2009","journal-title":"Circ. Res."},{"key":"2023062021505130900_ref31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1161\/01.RES.77.1.1","article-title":"Molecular regulation of atrioventricular valvuloseptal morphogenesis","volume":"77","author":"Eisenberg","year":"1995","journal-title":"Circ. 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Metab."},{"key":"2023062021505130900_ref39","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.ajhg.2007.08.005","article-title":"SERKAL syndrome: an autosomal-recessive disorder caused by a loss-of-function mutation in WNT4","volume":"82","author":"Mandel","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"2023062021505130900_ref40","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.ajhg.2017.10.006","article-title":"Monoallelic BMP2 variants predicted to result in haploinsufficiency cause craniofacial, skeletal, and cardiac features overlapping those of 20p12 deletions","volume":"101","author":"Tan","year":"2017","journal-title":"Am. J. Hum. 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