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Gata4 drives Hh-signaling for second heart field migration and outflow tract development

View ORCID ProfileJielin Liu, Henghui Cheng, View ORCID ProfileMenglan Xiang, Lun Zhou, Ke Zhang, Ivan P. Moskowitz, View ORCID ProfileLinglin Xie
doi: https://doi.org/10.1101/427336
Jielin Liu
1Department of Nutrition and Food Sciences, Texas A&M University, College Station, Texas, United States of America
4Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America
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  • ORCID record for Jielin Liu
Henghui Cheng
1Department of Nutrition and Food Sciences, Texas A&M University, College Station, Texas, United States of America
5Tongji Hospital, Huazhang University of Science and Technology, Wuhan, Hubei, China
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Menglan Xiang
2Department of Pathology, University of North Dakota, Grand Forks, North Dakota, United States of America
3ND-INBRE Bioinfomatic Core, University of North Dakota, Grand Forks, North Dakota, United States of America
4Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America
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Lun Zhou
4Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America
5Tongji Hospital, Huazhang University of Science and Technology, Wuhan, Hubei, China
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Ke Zhang
2Department of Pathology, University of North Dakota, Grand Forks, North Dakota, United States of America
3ND-INBRE Bioinfomatic Core, University of North Dakota, Grand Forks, North Dakota, United States of America
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Ivan P. Moskowitz
6Department of Pathology, The University of Chicago, Chicago, Illinois, United States of America
7Department of Pediatrics, The University of Chicago, Chicago, Illinois, United States of America
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Linglin Xie
1Department of Nutrition and Food Sciences, Texas A&M University, College Station, Texas, United States of America
4Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America
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  • For correspondence: Linglin.xie@tamu.edu
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Abstract

Dominant mutations of Gata4, an essential cardiogenic transcription factor (TF), cause outflow tract (OFT) defects in both human and mouse. We investigated the molecular mechanism underlying this requirement. Gata4 happloinsufficiency in mice caused OFT defects including double outlet right ventricle (DORV) and conal ventricular septum defects (VSDs). We found that Gata4 is required within Hedgehog (Hh)-receiving second heart field (SHF) progenitors for normal OFT alignment. Increased Pten-mediated cell-cycle transition, rescued atrial septal defects but not OFT defects in Gata4 heterozygotes. SHF Hh-receiving cells failed to migrate properly into the proximal OFT cushion in Gata4 heterozygote embryos. We find that Hh signaling and Gata4 genetically interact for OFT development. Gata4 and Smo double heterozygotes displayed more severe OFT abnormalities including persistent truncus arteriosus (PTA) whereas restoration of Hedgehog signaling rescued OFT defects in Gata4-mutant mice. In addition, enhanced expression of the Gata6 was observed in the SHF of the Gata4 heterozygotes. These results suggested a SHF regulatory network comprising of Gata4, Gata6 and Hh-signaling for OFT development. This study indicates that Gata4 potentiation of Hh signaling is a general feature of Gata4-mediated cardiac morphogenesis and provides a model for the molecular basis of CHD caused by dominant transcription factor mutations.

Author Summary Gata4 is an important protein that controls the development of the heart. Human who possess a single copy of Gata4 mutation display congenital heart defects (CHD), including the double outlet right ventricle (DORV). DORV is an alignment problem in which both the Aorta and Pulmonary Artery originate from the right ventricle, instead of originating from the left and the right ventricles, respectively. To study how Gata4 mutation causes DORV, we used a Gata4 mutant mouse model, which displays DORV. We showed that Gata4 is required in the cardiac precursor cells for the normal alignment of the great arteries. Although Gata4 mutation inhibits the rapid increase in number of the cardiac precursor cells, rescuing this defects does not recover the normal alignment of the great arteries. In addition, there is a movement problem of the cardiac precursor cells when migrating toward the great arteries during development. We further showed that a specific molecular signaling, Hh-signaling, is responsible to the Gata4 action in the cardiac precursor cells. Importantly, over-activating the Hh-signaling rescues the DORV in the Gata4 mutant embryos. This study provides an explanation for the ontogeny of CHD.

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Posted September 25, 2018.
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Gata4 drives Hh-signaling for second heart field migration and outflow tract development
Jielin Liu, Henghui Cheng, Menglan Xiang, Lun Zhou, Ke Zhang, Ivan P. Moskowitz, Linglin Xie
bioRxiv 427336; doi: https://doi.org/10.1101/427336
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Gata4 drives Hh-signaling for second heart field migration and outflow tract development
Jielin Liu, Henghui Cheng, Menglan Xiang, Lun Zhou, Ke Zhang, Ivan P. Moskowitz, Linglin Xie
bioRxiv 427336; doi: https://doi.org/10.1101/427336

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