{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:45:59Z","timestamp":1791290759835,"version":"4.3.0"},"reference-count":28,"publisher":"The Company of Biologists","issue":"6","license":[{"start":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T00:00:00Z","timestamp":1612828800000},"content-version":"vor","delay-in-days":239,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35 HL135778"],"award-info":[{"award-number":["R35 HL135778"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["W81XWH-17-1-0661"],"award-info":[{"award-number":["W81XWH-17-1-0661"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["T32 HD060600"],"award-info":[{"award-number":["T32 HD060600"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"WCM Medical Scientist Training Program"},{"DOI":"10.13039\/100004856","name":"New York State Department of Health","doi-asserted-by":"publisher","award":["C32558GG"],"award-info":[{"award-number":["C32558GG"]}],"id":[{"id":"10.13039\/100004856","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,6,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>The Gata4\/5\/6 sub-family of zinc finger transcription factors regulate many aspects of cardiogenesis. However, critical roles in extra-embryonic endoderm also challenge comprehensive analysis during early mouse cardiogenesis, while zebrafish models have previously relied on knockdown assays. We generated targeted deletions to disrupt each gata4\/5\/6 gene in zebrafish and analyzed cardiac phenotypes in single, double and triple mutants. The analysis confirmed that loss of gata5 causes cardia bifida and validated functional redundancies for gata5\/6 in cardiac precursor specification. Surprisingly, we discovered that gata4 is dispensable for early zebrafish development, while loss of one gata4 allele can suppress the bifid phenotype of the gata5 mutant. The gata4 mutants eventually develop an age-dependent cardiomyopathy. By combining combinations of mutant alleles, we show that cardiac specification depends primarily on an overall dosage of gata4\/5\/6 alleles rather than a specific gene. We also identify a specific role for gata6 in controlling ventricle morphogenesis through regulation of both the first and second heart field, while loss of both gata4\/6 eliminates the ventricle. Thus, different developmental programs are dependent on total dosage, certain pairs, or specific gata4\/5\/6 genes during embryonic cardiogenesis.<\/jats:p>\n               <jats:p>This article has an associated First Person interview with the first author of the paper.<\/jats:p>","DOI":"10.1242\/bio.053611","type":"journal-article","created":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T17:15:20Z","timestamp":1593018920000},"source":"Crossref","is-referenced-by-count":25,"title":["Specificity, redundancy and dosage thresholds among <i>gata4\/5\/6<\/i> genes during zebrafish cardiogenesis"],"prefix":"10.1242","volume":"9","author":[{"given":"Jessica","family":"Sam","sequence":"first","affiliation":[{"name":"Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily J.","family":"Mercer","sequence":"additional","affiliation":[{"name":"Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Torregroza","sequence":"additional","affiliation":[{"name":"Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly M.","family":"Banks","sequence":"additional","affiliation":[{"name":"Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7148-9849","authenticated-orcid":false,"given":"Todd","family":"Evans","sequence":"additional","affiliation":[{"name":"Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2020,6,24]]},"reference":[{"key":"2021042622475343600_BIO053611C1","doi-asserted-by":"publisher","first-page":"e82","DOI":"10.1093\/nar\/gkr218","article-title":"Efficient design and assembly of custom TALEN and other TAL effector-based constructs for DNA targeting","volume":"39","author":"Cermak","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"2021042622475343600_BIO053611C2","doi-asserted-by":"publisher","first-page":"W117","DOI":"10.1093\/nar\/gks608","article-title":"TAL Effector-Nucleotide Targeter (TALE-NT) 2.0: tools for TAL effector design and target prediction","volume":"40","author":"Doyle","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2021042622475343600_BIO053611C3","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1016\/j.ydbio.2007.03.007","article-title":"nanos1 is required to maintain oocyte production in adult zebrafish","volume":"305","author":"Draper","year":"2007","journal-title":"Dev. Biol."},{"key":"2021042622475343600_BIO053611C4","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1016\/j.ydbio.2007.09.018","article-title":"Gata5 and Gata6 are functionally redundant in zebrafish for specification of cardiomyocytes","volume":"312","author":"Holtzinger","year":"2007","journal-title":"Dev. Biol."},{"key":"2021042622475343600_BIO053611C5","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1242\/dev.126.1.75","article-title":"Control of early cardiac-specific transcription of Nkx2-5 by a GATA-dependent enhancer","volume":"126","author":"Lien","year":"1999","journal-title":"Development"},{"key":"2021042622475343600_BIO053611C6","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/B978-0-12-387786-4.00008-7","article-title":"Transcription factor pathways and congenital heart disease","volume":"100","author":"McCulley","year":"2012","journal-title":"Curr. Top. Dev. Biol."},{"key":"2021042622475343600_BIO053611C7","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1101\/gad.11.8.1061","article-title":"Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis","volume":"11","author":"Molkentin","year":"1997","journal-title":"Genes Dev."},{"key":"2021042622475343600_BIO053611C8","doi-asserted-by":"publisher","first-page":"W401","DOI":"10.1093\/nar\/gku410","article-title":"CHOPCHOP: a CRISPR\/Cas9 and TALEN web tool for genome editing","volume":"42","author":"Montague","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"2021042622475343600_BIO053611C9","doi-asserted-by":"publisher","first-page":"e0128105","DOI":"10.1371\/journal.pone.0128105","article-title":"Novel roles of GATA4\/6 in the postnatal heart identified through temporally controlled, cardiomyocyte-specific gene inactivation by adeno-associated virus delivery of Cre recombinase","volume":"10","author":"Prendiville","year":"2015","journal-title":"PLoS ONE"},{"key":"2021042622475343600_BIO053611C10","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.ydbio.2004.08.008","article-title":"GATA4 is a dosage-sensitive regulator of cardiac morphogenesis","volume":"275","author":"Pu","year":"2004","journal-title":"Dev. Biol."},{"key":"2021042622475343600_BIO053611C11","doi-asserted-by":"publisher","first-page":"2983","DOI":"10.1101\/gad.13.22.2983","article-title":"Gata 5 is required for the development of the heart and endoderm in zebrafish","volume":"13","author":"Reiter","year":"1999","journal-title":"Genes Dev."},{"key":"2021042622475343600_BIO053611C12","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"2021042622475343600_BIO053611C13","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1007\/s12519-014-0511-z","article-title":"Novel and functional DNA sequence variants within the GATA5 gene promoter in ventricular septal defects","volume":"10","author":"Shan","year":"2014","journal-title":"World J. Pediatr."},{"key":"2021042622475343600_BIO053611C14","doi-asserted-by":"publisher","first-page":"1765","DOI":"10.1074\/jbc.M109.038539","article-title":"Gata4 and Gata5 cooperatively regulate cardiac myocyte proliferation in mice","volume":"285","author":"Singh","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2021042622475343600_BIO053611C15","doi-asserted-by":"publisher","first-page":"2238","DOI":"10.1128\/MCB.16.5.2238","article-title":"A palindromic regulatory site within vertebrate GATA-1 promoters requires both zinc fingers of the GATA-1 DNA-binding domain for high-affinity interaction","volume":"16","author":"Trainor","year":"1996","journal-title":"Mol. Cell. Biol."},{"key":"2021042622475343600_BIO053611C16","doi-asserted-by":"publisher","first-page":"dev164384","DOI":"10.1242\/dev.164384","article-title":"GATA transcription factors in development and disease","volume":"145","author":"Tremblay","year":"2018","journal-title":"Development"},{"key":"2021042622475343600_BIO053611C17","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1016\/j.cub.2004.12.083","article-title":"Hand2 regulates epithelial formation during myocardial differentiation","volume":"15","author":"Trinh","year":"2005","journal-title":"Curr. Biol."},{"key":"2021042622475343600_BIO053611C18","doi-asserted-by":"publisher","first-page":"4056","DOI":"10.1038\/s41467-019-12028-5","article-title":"CRISPR-Cas9-based mutagenesis frequently provokes on-target mRNA misregulation","volume":"10","author":"Tuladhar","year":"2019","journal-title":"Nat. Commun."},{"key":"2021042622475343600_BIO053611C19","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1161\/CIRCRESAHA.110.220764","article-title":"The transcription factor GATA-6 regulates pathological cardiac hypertrophy","volume":"107","author":"van Berlo","year":"2010","journal-title":"Circ. Res."},{"key":"2021042622475343600_BIO053611C20","doi-asserted-by":"publisher","first-page":"12573","DOI":"10.1073\/pnas.0400752101","article-title":"GATA4 is essential for formation of the proepicardium and regulates cardiogenesis","volume":"101","author":"Watt","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042622475343600_BIO053611C21","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1097\/HCO.0b013e328337b4ce","article-title":"The molecular genetics of congenital heart disease: a review of recent developments","volume":"25","author":"Wolf","year":"2010","journal-title":"Curr. Opin. Cardiol."},{"key":"2021042622475343600_BIO053611C22","doi-asserted-by":"publisher","first-page":"11189","DOI":"10.1073\/pnas.0604604103","article-title":"A threshold of GATA4 and GATA6 expression is required for cardiovascular development","volume":"103","author":"Xin","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042622475343600_BIO053611C23","doi-asserted-by":"publisher","first-page":"4562","DOI":"10.1128\/MCB.12.10.4562","article-title":"Distinct roles for the two cGATA-1 finger domains","volume":"12","author":"Yang","year":"1992","journal-title":"Mol. Cell. Biol."},{"key":"2021042622475343600_BIO053611C24","doi-asserted-by":"publisher","first-page":"1522","DOI":"10.1172\/JCI23769","article-title":"Morphogenesis of the right ventricle requires myocardial expression of Gata4","volume":"115","author":"Zeisberg","year":"2005","journal-title":"J. Clin. Invest."},{"key":"2021042622475343600_BIO053611C25","doi-asserted-by":"publisher","first-page":"2622","DOI":"10.1128\/MCB.25.7.2622-2631.2005","article-title":"GATA6 is essential for embryonic development of the liver but dispensable for early heart formation","volume":"25","author":"Zhao","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"2021042622475343600_BIO053611C26","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1016\/j.ydbio.2008.03.013","article-title":"Loss of both GATA4 and GATA6 blocks cardiac myocyte differentiation and results in acardia in mice","volume":"317","author":"Zhao","year":"2008","journal-title":"Dev. Biol."},{"key":"2021042622475343600_BIO053611C27","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1038\/nature10094","article-title":"Latent TGF-\u03b2 binding protein 3 identifies a second heart field in zebrafish","volume":"474","author":"Zhou","year":"2011","journal-title":"Nature"},{"key":"2021042622475343600_BIO053611C28","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/B978-0-12-801185-0.00011-8","article-title":"The iCRISPR platform for rapid genome editing in human pluripotent stem cells","volume":"546","author":"Zhu","year":"2014","journal-title":"Methods Enzymol."}],"container-title":["Biology Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/bio.053611","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.logists.com\/bio\/bio\/article-pdf\/doi\/10.1242\/bio.053611\/1837197\/bio053611.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.logists.com\/bio\/bio\/article-pdf\/doi\/10.1242\/bio.053611\/1837197\/bio053611.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T01:29:56Z","timestamp":1619486996000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/bio\/article\/9\/6\/bio053611\/222898\/Specificity-redundancy-and-dosage-thresholds-among"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,15]]},"references-count":28,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2020,6,15]]}},"URL":"https:\/\/doi.org\/10.1242\/bio.053611","relation":{},"ISSN":["2046-6390"],"issn-type":[{"value":"2046-6390","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,15]]},"article-number":"bio053611"}}