The AP-1 transcription factor component Fosl2 potentiates the rate of myocardial differentiation from the zebrafish second heart field

AbstractDominant 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 SummaryGata4 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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Gata4 potentiates second heart field proliferation and Hedgehog signaling for cardiac septation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1605137114 ◽

2017 ◽

Vol 114 (8) ◽

pp. E1422-E1431 ◽

Cited By ~ 24

Author(s):

Lun Zhou ◽

Jielin Liu ◽

Menglan Xiang ◽

Patrick Olson ◽

Alexander Guzzetta ◽

...

Keyword(s):

Cell Cycle ◽

Transcription Factor ◽

Hedgehog Signaling ◽

Cell Cycle Progression ◽

Regulatory Element ◽

Second Heart Field ◽

Heart Field ◽

Hh Signaling

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.

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AcvR1-mediated BMP signaling in second heart field is required for arterial pole development: Implications for myocardial differentiation and regional identity

Developmental Biology ◽

10.1016/j.ydbio.2014.03.008 ◽

2014 ◽

Vol 390 (2) ◽

pp. 191-207 ◽

Cited By ~ 11

Author(s):

Penny S. Thomas ◽

Sudha Rajderkar ◽

Jamie Lane ◽

Yuji Mishina ◽

Vesa Kaartinen

Keyword(s):

Regional Identity ◽

Bmp Signaling ◽

Second Heart Field ◽

Heart Field ◽

Myocardial Differentiation

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Spotlight on Isl1: A Key Player in Cardiovascular Development and Diseases

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.793605 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jie Ren ◽

Danxiu Miao ◽

Yanshu Li ◽

Rui Gao

Keyword(s):

Transcription Factor ◽

Regulatory Network ◽

Molecular Basis ◽

Marker Gene ◽

Cardiovascular Development ◽

Second Heart Field ◽

Multiple Organs ◽

Heart Field ◽

And Function ◽

Cardiac Transcription Factors

Cardiac transcription factors orchestrate a regulatory network controlling cardiovascular development. Isl1, a LIM-homeodomain transcription factor, acts as a key player in multiple organs during embryonic development. Its crucial roles in cardiovascular development have been elucidated by extensive studies, especially as a marker gene for the second heart field progenitors. Here, we summarize the roles of Isl1 in cardiovascular development and function, and outline its cellular and molecular modes of action, thus providing insights for the molecular basis of cardiovascular diseases.

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Lamb1a regulates atrial growth by limiting excessive, contractility-dependent second heart field addition during zebrafish heart development

10.1101/2021.03.10.434727 ◽

2021 ◽

Author(s):

Christopher J. Derrick ◽

Eric J. G. Pollitt ◽

Ashley Sanchez Sevilla Uruchurtu ◽

Farah Hussein ◽

Emily S. Noёl

Keyword(s):

Heart Development ◽

Cardiac Development ◽

Basement Membranes ◽

Atrioventricular Canal ◽

Cardiac Morphogenesis ◽

Heart Morphogenesis ◽

Second Heart Field ◽

Heart Field ◽

Heart Size ◽

Zebrafish Heart

AbstractDuring early vertebrate heart development, the heart transitions from a linear tube to a complex asymmetric structure. This process includes looping of the tube and ballooning of the emerging cardiac chambers, which occur simultaneously with growth of the heart. A key driver of cardiac growth is deployment of cells from the Second Heart Field (SHF) into both poles of the heart, with cardiac morphogenesis and growth intimately linked in heart development. Laminin is a core component of extracellular matrix (ECM) basement membranes, and although mutations in specific laminin subunits are linked with a variety of cardiac abnormalities, including congenital heart disease and dilated cardiomyopathy, no role for laminin has been identified in early vertebrate heart morphogenesis. We identified dynamic, tissue-specific expression of laminin subunit genes in the developing zebrafish heart, supporting a role for laminins in heart morphogenesis.lamb1amutants exhibit cardiomegaly from 2dpf onwards, with subsequent progressive defects in cardiac morphogenesis characterised by a failure of the chambers to compact around the developing atrioventricular canal. We show that loss oflamb1aresults in excess addition of SHF cells to the atrium, revealing that Lamb1a functions to limit heart size during cardiac development by restricting SHF addition to the venous pole.lamb1amutants exhibit hallmarks of altered haemodynamics, and specifically blocking cardiac contractility inlamb1amutants rescues heart size and atrial SHF addition. Furthermore, we identify that FGF and RA signalling, two conserved pathways promoting SHF addition, are regulated by heart contractility and are dysregulated inlamb1amutants, suggesting that laminin mediates interactions between SHF deployment, heart biomechanics, and biochemical signalling during heart development. Together, this describes the first requirement for laminins in early vertebrate heart morphogenesis, reinforcing the importance of specialised ECM composition in cardiac development.

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Expression of the BMP Receptor Alk3 in the Second Heart Field Is Essential for Development of the Dorsal Mesenchymal Protrusion and Atrioventricular Septation

Circulation Research ◽

10.1161/circresaha.112.300821 ◽

2013 ◽

Vol 112 (11) ◽

pp. 1420-1432 ◽

Cited By ~ 48

Author(s):

Laura E. Briggs ◽

Aimee L. Phelps ◽

Elizabeth Brown ◽

Jayant Kakarla ◽

Robert H. Anderson ◽

...

Keyword(s):

Second Heart Field ◽

Bmp Receptor ◽

Heart Field ◽

Dorsal Mesenchymal Protrusion ◽

Atrioventricular Septation

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Temporally Distinct Six2 -Positive Second Heart Field Progenitors Regulate Mammalian Heart Development and Disease

Cell Reports ◽

10.1016/j.celrep.2017.01.002 ◽

2017 ◽

Vol 18 (4) ◽

pp. 1019-1032 ◽

Cited By ~ 24

Author(s):

Zhengfang Zhou ◽

Jingying Wang ◽

Chaoshe Guo ◽

Weiting Chang ◽

Jian Zhuang ◽

...

Keyword(s):

Heart Development ◽

Second Heart Field ◽

Mammalian Heart ◽

Heart Field

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Loss of Wnt5a disrupts second heart field cell deployment and may contribute to OFT malformations in DiGeorge syndrome

Human Molecular Genetics ◽

10.1093/hmg/ddu584 ◽

2014 ◽

Vol 24 (6) ◽

pp. 1704-1716 ◽

Cited By ~ 32

Author(s):

Tanvi Sinha ◽

Ding Li ◽

Magali Théveniau-Ruissy ◽

Mary R. Hutson ◽

Robert G. Kelly ◽

...

Keyword(s):

Digeorge Syndrome ◽

Second Heart Field ◽

Heart Field

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A Boolean Model of the Cardiac Gene Regulatory Network Determining First and Second Heart Field Identity

PLoS ONE ◽

10.1371/journal.pone.0046798 ◽

2012 ◽

Vol 7 (10) ◽

pp. e46798 ◽

Cited By ~ 36

Author(s):

Franziska Herrmann ◽

Alexander Groß ◽

Dao Zhou ◽

Hans A. Kestler ◽

Michael Kühl

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Boolean Model ◽

Second Heart Field ◽

Cardiac Gene ◽

Heart Field ◽

Gene Regulatory

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Cardiac embryogenesis

ESC CardioMed ◽

10.1093/med/9780198784906.003.0004_update_001 ◽

2018 ◽

pp. 33-36

Author(s):

Robert G. Kelly

Keyword(s):

Progenitor Cells ◽

Progenitor Cell ◽

Congenital Heart ◽

Heart Defects ◽

Embryonic Heart ◽

Heart Tube ◽

Second Heart Field ◽

Heart Field ◽

Cell Niche ◽

The Right

The embryonic heart forms in anterior lateral splanchnic mesoderm and is derived from Mesp1-expressing progenitor cells. During embryonic folding, the earliest differentiating progenitor cells form the linear heart tube in the ventral midline. The heart tube extends in length and loops to the right as new myocardium is progressively added at the venous and arterial poles from multipotent second heart field cardiovascular progenitor cells in contiguous pharyngeal mesoderm. While the linear heart tube gives rise to the left ventricle, the right ventricle, outflow tract, and a large part of atrial myocardium are derived from the second heart field. Progressive myocardial differentiation is controlled by intercellular signals within the progenitor cell niche. The embryonic heart is the template for septation and growth of the four-chambered definitive heart and defects in progenitor cell deployment result in a spectrum of common forms of congenital heart defects.

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