Gata4 potentiates second heart field proliferation and Hedgehog signaling for cardiac septation.
GATA4, an essential cardiogenic transcription factor, provides a model for dominant transcription factor mutations in human disease. Dominant GATA4 mutations cause congenital heart disease (CHD), specifically atrial and atrioventricular septal defects (ASDs and AVSDs). We found that second heart field (SHF)-specificGata4heterozygote embryos recapitulated the AVSDs observed in germlineGata4heterozygote embryos. A proliferation defect of SHF atrial septum progenitors and hypoplasia of the dorsal mesenchymal protrusion, rather than anlage of the atrioventricular septum, were observed in this model. Knockdown of the cell-cycle repressor phosphatase and tensin homolog (Pten) restored cell-cycle progression and rescued the AVSDs.Gata4mutants also demonstrated Hedgehog (Hh) signaling defects. Gata4 acts directly upstream ofHhcomponents: Gata4 activated acis-regulatory element atGli1in vitro and occupied the element in vivo. Remarkably, SHF-specific constitutive Hh signaling activation rescued AVSDs in Gata4 SHF-specific heterozygous knockout embryos. Pten expression was unchanged inSmoothenedmutants, and Hh pathway genes were unchanged inPtenmutants, suggesting pathway independence. Thus, both the cell-cycle and Hh-signaling defects caused by dominantGata4mutations were required for CHD pathogenesis, suggesting a combinatorial model of disease causation by transcription factor haploinsufficiency.
Department of Basic Sciences, University of North Dakota, Grand Forks, ND 58202.|Department of Gerontology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
Lun
L
Zhou
Department of Nutrition and Food Sciences, Texas A&M University, College Station, TX 77843.
Jielin
J
Liu
Department of Basic Sciences, University of North Dakota, Grand Forks, ND 58202.
Menglan
M
Xiang
Department of Basic Sciences, University of North Dakota, Grand Forks, ND 58202.
Patrick
P
Olson
Department of Pediatrics, The University of Chicago, Chicago, IL 60637.|Department of Pathology, The University of Chicago, Chicago, IL 60637.|Department of Human Genetics, The University of Chicago, Chicago, IL 60637.
Alexander
A
Guzzetta
Department of Pathology, University of North Dakota, Grand Forks, ND 58202.|North Dakota Idea Network of Biomedical Research Excellence Bioinformatics Core; University of North Dakota, Grand Forks ND 58202.
Ke
K
Zhang
Department of Pediatrics, The University of Chicago, Chicago, IL 60637; linglin.xie@tamu.edu imoskowitz@uchicago.edu.|Department of Pathology, The University of Chicago, Chicago, IL 60637.|Department of Human Genetics, The University of Chicago, Chicago, IL 60637.
Ivan P
IP
Moskowitz
Department of Basic Sciences, University of North Dakota, Grand Forks, ND 58202; linglin.xie@tamu.edu imoskowitz@uchicago.edu.|Department of Nutrition and Food Sciences, Texas A&M University, College Station, TX 77843.
Linglin
L
Xie
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology*; D050991:GATA4 Transcription Factor / Q000378:metabolism*; D006321:Heart / Q000502:physiology*; D006346:Heart Septum / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D053823:Hedgehog Proteins; D014157:Transcription Factors
ASDs; Gata4; Hedgehog signaling; cell cycle; second heart field