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

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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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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The amphibian second heart field: Xenopus islet-1 is required for cardiovascular development

Developmental Biology ◽

10.1016/j.ydbio.2007.08.004 ◽

2007 ◽

Vol 311 (2) ◽

pp. 297-310 ◽

Cited By ~ 87

Author(s):

Thomas Brade ◽

Susanne Gessert ◽

Michael Kühl ◽

Petra Pandur

Keyword(s):

Cardiovascular Development ◽

Second Heart Field ◽

Heart Field ◽

Islet 1

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Hedgehog signaling activates a heterochronic gene regulatory network to control differentiation timing across lineages

10.1101/270751 ◽

2018 ◽

Cited By ~ 1

Author(s):

Megan Rowton ◽

Carlos Perez-Cervantes ◽

Ariel Rydeen ◽

Suzy Hur ◽

Jessica Jacobs-Li ◽

...

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Hedgehog Signaling ◽

Cardiomyocyte Differentiation ◽

Cardiac Progenitors ◽

Second Heart Field ◽

Heart Field ◽

Gene Regulatory ◽

Hh Signaling

SUMMARYHeterochrony, defined as differences in the timing of developmental processes, impacts organ development, homeostasis, and regeneration. The molecular basis of heterochrony in mammalian tissues is poorly understood. We report that Hedgehog signaling activates a heterochronic pathway that controls differentiation timing in multiple lineages. A differentiation trajectory from second heart field cardiac progenitors to first heart field cardiomyocytes was identified by single-cell transcriptional profiling in mouse embryos. A survey of developmental signaling pathways revealed specific enrichment for Hedgehog signaling targets in cardiac progenitors. Removal of Hh signaling caused loss of progenitor and precocious cardiomyocyte differentiation gene expression in the second heart field in vivo. Introduction of active Hh signaling to mESC-derived progenitors, modelled by transient expression of the Hh-dependent transcription factor GLI1, delayed differentiation in cardiac and neural lineages in vitro. A shared GLI1-dependent network in both cardiac and neural progenitors was enriched with FOX family transcription factors. FOXF1, a GLI1 target, was sufficient to delay onset of the cardiomyocyte differentiation program in progenitors, by epigenetic repression of cardiomyocyte-specific enhancers. Removal of active Hh signaling or Foxf1 expression from second heart field progenitors caused precocious cardiac differentiation in vivo, establishing a mechanism for resultant Congenital Heart Disease. Together, these studies suggest that Hedgehog signaling directly activates a gene regulatory network that functions as a heterochronic switch to control differentiation timing across developmental lineages.

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The Genetics and Biology of FOXL2

Sexual Development ◽

10.1159/000519836 ◽

2021 ◽

pp. 1-10

Author(s):

Elena J. Tucker

Keyword(s):

Transcription Factor ◽

Cell Cycle Progression ◽

Target Genes ◽

Ovarian Function ◽

Multiple Organs ◽

Sex Development ◽

Eyelid Development ◽

Granulosa Cell Tumours ◽

And Function

FOXL2 encodes a transcription factor that regulates a wide array of target genes including those involved in sex development, eyelid development, ovarian function and maintenance, genomic integrity as well as cellular pathways such as cell-cycle progression, proliferation, and apoptosis. The role of FOXL2 has been widely studied in humans and animals. Consistent with its role in ovarian and eyelid development, over 100 germline variants in FOXL2 are associated with blepharophimosis, ptosis, and epicanthus inversus syndrome in humans, an autosomal dominant condition characterised by ovarian dysgenesis/premature ovarian insufficiency, as well as defective eyelid development. Reflecting its role in apoptosis and proliferation, a somatic variant in FOXL2 causes adult granulosa cell tumours in humans. Despite being widely studied and having clear relevance to human disease, much remains unknown about the genes FOXL2 regulates and how it exerts its wide-reaching effect on multiple organs. This review focuses on FOXL2 and its varied roles as a transcription factor in sex determination, ovarian maintenance and function, eyelid development, genome integrity, and cell regulation, followed by discussion of the in vivo disruption of FOXL2 in humans and other species.

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

10.1101/427336 ◽

2018 ◽

Author(s):

Jielin Liu ◽

Henghui Cheng ◽

Menglan Xiang ◽

Lun Zhou ◽

Ke Zhang ◽

...

Keyword(s):

Transcription Factor ◽

Right Ventricle ◽

Double Outlet Right Ventricle ◽

Precursor Cells ◽

Outflow Tract ◽

Second Heart Field ◽

Heart Field ◽

Hh Signaling ◽

The Right ◽

Cardiac Precursor Cells

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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Abstract 541: A Hedgehog-signaling Dependent Gene Regulatory Network Directly Delays Second Heart Field Differentiation to Prevent Congenital Heart Disease

Circulation Research ◽

10.1161/res.127.suppl_1.541 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Megan Rowton ◽

Ariel Rydeen ◽

Perez-Cervantes Carlos ◽

Nikita Deng ◽

Emery Lu ◽

...

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Transcriptional Profiling ◽

Cardiomyocyte Differentiation ◽

Cardiac Progenitors ◽

Second Heart Field ◽

Heart Field ◽

Gene Regulatory ◽

Hh Signaling

The first heart field (FHF) and the second heart field (SHF) comprise the major progenitor pools for the developing vertebrate heart. We investigated the delayed differentiation of the SHF relative to the FHF, a major distinguishing feature of these fields. Single-cell transcriptional profiling of the SHF revealed a differentiation trajectory of SHF progenitors to cardiomyocytes. Hedgehog (Hh) signaling was highly enriched in the progenitor state in signaling pathway analysis, suggesting a possible role in cardiomyocyte differentiation control. Transcriptional profiling of the SHF following removal of active Hh signaling in vivo revealed inappropriate cardiomyocyte gene expression. We observed precocious cardiomyocyte differentiation in the SHF in vivo in Hh mutants, which led to Congenital Heart Disease (CHD). Modeling active Hh signaling in a novel mouse embryonic stem cell (mESC) line through transient expression of the activating Hh transcription factor (TF), GLI1, in cardiac progenitors delayed the onset of cardiomyocyte differentiation. GLI1 directly activated a progenitor-specific gene regulatory network, dominated by repressive TFs, that prevented the acquisition of the cardiomyocyte gene regulatory network. Maintained expression of one GLI1 target TF, FOXF1, repressed the cardiomyocyte differentiation program. FOXF1 binding sites were identified at putative regulatory elements near repressed cardiac genes involved in contraction, electrical impulse propagation and transcriptional regulation. Finally, FOXF1 repressed the activity of these elements in vitro , indicating that FOXF1 can directly repress the activation of genes essential for cardiomyocyte differentiation. Together, these results indicate that a Hh-dependent gene regulatory network including transcriptional repressors directly delays the onset of cardiomyocyte gene expression to delay SHF differentiation. Abrogation of Hh signaling and the resultant premature differentiation of cardiac progenitors provides a molecular mechanism for the ontogeny of some CHD.

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Functional divergence of paralogous transcription factors supported the evolution of biomineralization in echinoderms

eLife ◽

10.7554/elife.32728 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 6

Author(s):

Jian Ming Khor ◽

Charles A Ettensohn

Keyword(s):

Transcription Factor ◽

Regulatory Network ◽

Function Analysis ◽

Functional Divergence ◽

Duplication Event ◽

Functional Specialization ◽

Gene Duplication Event ◽

Morphological Novelty ◽

Gene Regulatory ◽

And Function

Alx1 is a pivotal transcription factor in a gene regulatory network that controls skeletogenesis throughout the echinoderm phylum. We performed a structure-function analysis of sea urchin Alx1 using a rescue assay and identified a novel, conserved motif (Domain 2) essential for skeletogenic function. The paralogue of Alx1, Alx4, was not functionally interchangeable with Alx1, but insertion of Domain 2 conferred robust skeletogenic function on Alx4. We used cross-species expression experiments to show that Alx1 proteins from distantly related echinoderms are not interchangeable, although the sequence and function of Domain 2 are highly conserved. We also found that Domain 2 is subject to alternative splicing and provide evidence that this domain was originally gained through exonization. Our findings show that a gene duplication event permitted the functional specialization of a transcription factor through changes in exon-intron organization and thereby supported the evolution of a major morphological novelty.

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

Development ◽

10.1242/dev.126136 ◽

2016 ◽

Vol 143 (1) ◽

pp. 113-122 ◽

Cited By ~ 19

Author(s):

Leila Jahangiri ◽

Michka Sharpe ◽

Natasha Novikov ◽

Juan Manuel González-Rosa ◽

Asya Borikova ◽

...

Keyword(s):

Transcription Factor ◽

Second Heart Field ◽

Heart Field ◽

Myocardial Differentiation

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Genetic and Cellular Interaction During Cardiovascular Development Implicated in Congenital Heart Diseases

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.653244 ◽

2021 ◽

Vol 8 ◽

Author(s):

Kazuki Kodo ◽

Keiko Uchida ◽

Hiroyuki Yamagishi

Keyword(s):

Neural Crest ◽

Congenital Heart ◽

Cellular Interaction ◽

Cardiovascular Development ◽

Cardiac Neural Crest ◽

Second Heart Field ◽

Genomic Architecture ◽

Heart Field ◽

First Heart Field ◽

Mutation Analyses

Congenital heart disease (CHD) is the most common life-threatening congenital anomaly. CHD occurs due to defects in cardiovascular development, and the majority of CHDs are caused by a multifactorial inheritance mechanism, which refers to the interaction between genetic and environmental factors. During embryogenesis, the cardiovascular system is derived from at least four distinct cell lineages: the first heart field, second heart field, cardiac neural crest, and proepicardial organ. Understanding the genes involved in each lineage is essential to uncover the genomic architecture of CHD. Therefore, we provide an overview of recent research progress using animal models and mutation analyses to better understand the molecular mechanisms and pathways linking cardiovascular development and CHD. For example, we highlight our recent work on genes encoding three isoforms of inositol 1,4,5-trisphosphate receptors (IP3R1, 2, and 3) that regulate various vital and developmental processes, which have genetic redundancy during cardiovascular development. Specifically, IP3R1 and 2 have redundant roles in the atrioventricular cushion derived from the first heart field lineage, whereas IP3R1 and 3 exhibit redundancy in the right ventricle and the outflow tract derived from the second heart field lineage, respectively. Moreover, 22q11.2 deletion syndrome (22q11DS) is highly associated with CHD involving the outflow tract, characterized by defects of the cardiac neural crest lineage. However, our studies have shown that TBX1, a major genetic determinant of 22q11DS, was not expressed in the cardiac neural crest but rather in the second heart field, suggesting the importance of the cellular interaction between the cardiac neural crest and the second heart field. Comprehensive genetic analysis using the Japanese genome bank of CHD and mouse models revealed that a molecular regulatory network involving GATA6, FOXC1/2, TBX1, SEMA3C, and FGF8 was essential for reciprocal signaling between the cardiac neural crest and the second heart field during cardiovascular development. Elucidation of the genomic architecture of CHD using induced pluripotent stem cells and next-generation sequencing technology, in addition to genetically modified animal models and human mutation analyses, would facilitate the development of regenerative medicine and/or preventive medicine for CHD in the near future.

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