{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T22:43:41Z","timestamp":1772664221973,"version":"3.50.1"},"reference-count":50,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T00:00:00Z","timestamp":1721001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"MICIU\/AEI\/10.13039\/501100011033 and La Caixa Research Health Foundation","doi-asserted-by":"publisher","award":["PID2022-104776RB-100"],"award-info":[{"award-number":["PID2022-104776RB-100"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"MICIU\/AEI\/10.13039\/501100011033 and La Caixa Research Health Foundation","doi-asserted-by":"publisher","award":["CB16\/11\/00399"],"award-info":[{"award-number":["CB16\/11\/00399"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"MICIU\/AEI\/10.13039\/501100011033 and La Caixa Research Health Foundation","doi-asserted-by":"publisher","award":["CEX2020001041-S"],"award-info":[{"award-number":["CEX2020001041-S"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Regional Development Fund","award":["PID2022-104776RB-100"],"award-info":[{"award-number":["PID2022-104776RB-100"]}]},{"name":"European Regional Development Fund","award":["CB16\/11\/00399"],"award-info":[{"award-number":["CB16\/11\/00399"]}]},{"name":"European Regional Development Fund","award":["CEX2020001041-S"],"award-info":[{"award-number":["CEX2020001041-S"]}]},{"name":"MCIU\/AEI\/10.13039\/501100011033","award":["PID2022-104776RB-100"],"award-info":[{"award-number":["PID2022-104776RB-100"]}]},{"name":"MCIU\/AEI\/10.13039\/501100011033","award":["CB16\/11\/00399"],"award-info":[{"award-number":["CB16\/11\/00399"]}]},{"name":"MCIU\/AEI\/10.13039\/501100011033","award":["CEX2020001041-S"],"award-info":[{"award-number":["CEX2020001041-S"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCDD"],"abstract":"<jats:p>Genome-wide association studies and experimental mouse models implicate the MIB1 and GATA6 genes in congenital heart disease (CHD). Their close physical proximity and conserved synteny suggest that these two genes might be involved in analogous cardiac developmental processes. Heterozygous Gata6 loss-of-function mutations alone or humanized Mib1 mutations in a NOTCH1-sensitized genetic background cause bicuspid aortic valve (BAV) and a membranous ventricular septal defect (VSD), consistent with MIB1 and NOTCH1 functioning in the same pathway. To determine if MIB1-NOTCH and GATA6 interact in valvular and septal development, we generated compound heterozygote mice carrying different Mib1 missense (Mib1K735R and Mib1V943F) or nonsense (Mib1R530X) mutations with the Gata6STOP\/+ heterozygous null mutation. Combining Mib1R530X\/+ or Mib1K735R\/+ with Gata6STOP\/+ does not affect Gata6STOP\/+ single mutant phenotypes. In contrast, combining Mib1V943F\/+ with Gata6STOP\/+ decreases the incidence of BAV and VSD by 50%, suggesting a suppressive effect of Mib1V943F\/+ on Gata6STOP\/+. Transcriptomic and functional analyses revealed that while the EMT pathway term is depleted in the Gata6STOP\/+ mutant, introducing the Mib1V943F variant robustly enriches this term, consistent with the Mib1V943F\/+ phenotypic suppression of Gata6STOP\/+. Interestingly, combined Notch1 and Gata6 insufficiency led to a nearly fully penetrant VSD but did not affect the BAV phenotype, underscoring the complex functional relationship between MIB1, NOTCH, and GATA6 in valvular and septal development.<\/jats:p>","DOI":"10.3390\/jcdd11070223","type":"journal-article","created":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T12:44:36Z","timestamp":1721047476000},"page":"223","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Intricate MIB1-NOTCH-GATA6 Interactions in Cardiac Valvular and Septal Development"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4227-8484","authenticated-orcid":false,"given":"Rebeca","family":"Pi\u00f1eiro-Sabar\u00eds","sequence":"first","affiliation":[{"name":"Intercellular Signaling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fern\u00e1ndez Almagro 3, 28029 Madrid, Spain"},{"name":"Ciber de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Melchor Fern\u00e1ndez Almagro 3, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2808-8422","authenticated-orcid":false,"given":"Donal","family":"MacGrogan","sequence":"additional","affiliation":[{"name":"Intercellular Signaling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fern\u00e1ndez Almagro 3, 28029 Madrid, Spain"},{"name":"Ciber de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Melchor Fern\u00e1ndez Almagro 3, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6761-7265","authenticated-orcid":false,"given":"Jos\u00e9 Luis","family":"de la Pompa","sequence":"additional","affiliation":[{"name":"Intercellular Signaling in Cardiovascular Development & Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fern\u00e1ndez Almagro 3, 28029 Madrid, Spain"},{"name":"Ciber de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Melchor Fern\u00e1ndez Almagro 3, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1136\/heartjnl-2016-309916","article-title":"Contemporary natural history of bicuspid aortic valve disease: A systematic review","volume":"103","author":"Masri","year":"2017","journal-title":"Heart"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.jacc.2014.04.073","article-title":"A roadmap to investigate the genetic basis of bicuspid aortic valve and its complications: Insights from the International BAVCon (Bicuspid Aortic Valve Consortium)","volume":"64","author":"Prakash","year":"2014","journal-title":"J. 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