The zebrafish as a model for cardiac development and regeneration

2018 ◽  
Author(s):  
Bill Chaudhry ◽  
José Luis de la Pompa ◽  
Nadia Mercader
Keyword(s):  
Heart Development ◽  
Cardiac Development ◽  
Model Organism ◽  
Laboratory Model ◽  
Developmental Studies ◽  
Sequencing Technologies ◽  
Technological Advances ◽  
The Common ◽  
Zebrafish Heart

The zebrafish has become an established laboratory model for developmental studies and is increasingly used to model aspects of human development and disease. However, reviewers and grant funding bodies continue to speculate on the utility of this Himalayan minnow. In this chapter we explain the similarities and differences between the heart from this distantly related vertebrate and the mammalian heart, in order to reveal the common fundamental processes and to prevent misleading extrapolations. We provide an overview of zebrafish including their husbandry, development, peculiarities of their genome, and technological advances, which make them a highly tractable laboratory model for heart development and disease. We discuss the controversies around morphants and mutants, and relate the development and structures of the zebrafish heart to mammalian counterparts. Finally, we give an overview of regeneration in the zebrafish heart and speculate on the role of the model organism in next-generation sequencing technologies.

Abstract 257: Clonal Analysis Of Multipotent Cardiovascular Progenitors That Generate Cardiomyocytes During Development

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Konstantina Ioanna Sereti ◽  
Paniz Kamran Rashani ◽  
Peng Zhao ◽  
Reza Ardehali
Keyword(s):  
Single Cell ◽  
Heart Development ◽  
Cardiac Development ◽  
Clonal Analysis ◽  
Cardiac Cells ◽  
Single Cell Level ◽  
Reporter System ◽  
Cell Level ◽  
Cardiac Progenitors

It has been proposed that cardiac development in lower vertebrates is driven by the proliferation of cardiomyocytes. Similarly, cycling myocytes have been suggested to direct cardiac regeneration in neonatal mice after injury. Although, the role of cardiomyocyte proliferation in cardiac tissue generation during development has been well documented, the extent of this contribution as well as the role of other cell types, such as progenitor cells, still remains controversial. Here we used a novel stochastic four-color Cre-dependent reporter system (Rainbow) that allows labeling at a single cell level and retrospective analysis of the progeny. Cardiac progenitors expressing Mesp1 or Nkx2.5 were shown to be a source of cardiomyocytes during embryonic development while the onset of αMHC expression marked the developmental stage where the capacity of cardiac cells to proliferate diminishes significantly. Through direct clonal analysis we provide strong evidence supporting that cardiac progenitors, as opposed to mature cardiomyocytes, are the main source of cardiomyocytes during cardiac development. Moreover, we have identified quadri-, tri-, bi, and uni-potent progenitors that at a single cell level can generate cardiomyocytes, fibroblasts, endothelial and smooth muscle cells. Although existing cardiomyocytes undergo limited proliferation, our data indicates that it is mainly the progenitors that contribute to heart development. Furthermore, we show that the limited proliferation capacity of cardiomyocytes observed during normal development was enhanced following neonatal cardiac injury allowing almost complete regeneration of the scared tissue. However, this ability was largely absent in adult injured hearts. Detailed characterization of dividing cardiomyocytes and proliferating progenitors would greatly benefit the development of novel therapeutic options for cardiovascular diseases.

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

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.

Abstract 052: Epicardial-derived Adrenomedullin Drives Cardiac Hyperplasia During Embryogenesis

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Sarah E Wetzel-Strong ◽  
Manyu Li ◽  
Toshio Nishikimi ◽  
Kathleen M Caron
Keyword(s):  
Embryonic Development ◽  
Heart Development ◽  
Cardiac Development ◽  
Lymphatic Vessels ◽  
Heart Weight ◽  
Cardiovascular Development ◽  
Proliferating Cells ◽  
Over Expression ◽  
Knockout Animals

The multi-functional peptide adrenomedullin ( Adm = gene, AM = protein) plays important roles in embryonic development and disease. Previous studies demonstrated that Adm knockout mice die at embryonic day 13.5 with small, disorganized hearts and hypoplastic lymphatic vessels, highlighting the importance of this peptide in normal cardiovascular development. Since Adm knockout animals are embryonic lethal, our goal was to generate and characterize a novel model of Adm over-expression to study the role of Adm during development and disease processes. Through gene targeting techniques, we generated a novel mouse model of Adm over-expression, abbreviated as Adm hi/hi . When we assessed gene expression of Adm from 10 different tissues, we found Adm hi/hi mice express 3- to 15-fold more Adm than wildtype littermates. Additionally, peptide levels of AM in lung and kidney, as well as circulating plasma levels of AM were elevated 3-fold over wildtype mice, indicating a functional increase in AM. Our initial analysis revealed that adult Adm hi/hi mice have larger heart weight to body weight ratios than wildtype littermates (4.93±0.23 vs. 5.96±0.29, n = 11-12). We found that compared to wildtype, Adm hi/hi embryos have more proliferating cells during heart development (14.46±1.11 vs. 31.97±2.84, n=4), indicating that hyperplasia drives Adm hi/hi heart enlargement. By crossing the Adm hi/hi line to different tissue-specific Cre lines, we were able to excise the stabilizing bovine growth hormone 3’UTR, thereby returning Adm expression levels back to wildtype in cells with active Cre recombinase. Using this approach, we identified the epicardium as a major source of AM during cardiac development. In conclusion, we found that AM derived primarily from the epicardium drives cardiac hyperplasia during embryonic development resulting in persistent, enlarged hearts of adult Adm hi/hi mice. Since our Adm hi/hi mice recapitulate the 3-fold plasma elevation of AM observed during human disease, this mouse line will be a useful tool for studying the role of elevated AM during disease.

The Role of Shear Stress on ET-1, KLF2, and NOS-3 Expression in the Developing Cardiovascular System of Chicken Embryos in a Venous Ligation Model

Physiology ◽  
2007 ◽  
Vol 22 (6) ◽  
pp. 380-389 ◽  
Author(s):  
Bianca C. W. Groenendijk ◽  
Kim Van der Heiden ◽  
Beerend P. Hierck ◽  
Robert E. Poelmann
Keyword(s):  
Shear Stress ◽  
Heart Development ◽  
Cardiac Development ◽  
Background Information ◽  
Endothelial Shear Stress ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Cardiovascular Anomalies ◽  
Chicken Model

In this review, the role of wall shear stress in the chicken embryonic heart is analyzed to determine its effect on cardiac development through regulating gene expression. Therefore, background information is provided for fluid dynamics, normal chicken and human heart development, cardiac malformations, cardiac and vitelline blood flow, and a chicken model to induce cardiovascular anomalies. A set of endothelial shear stress-responsive genes coding for endothelin-1 (ET-1), lung Krüppel-like factor (LKLF/KLF2), and endothelial nitric oxide synthase (eNOS/NOS-3) are active in development and are specifically addressed.

scholarly journals The role of KMT2D and KDM6A in cardiac development: A cross-species analysis in humans, mice, and zebrafish

2020 ◽  
Author(s):  
Rwik Sen ◽  
Ezra Lencer ◽  
Elizabeth A. Geiger ◽  
Kenneth L. Jones ◽  
Tamim H. Shaikh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Development ◽  
Target Genes ◽  
Cardiac Development ◽  
Heart Defects ◽  
Neural Crest Cell ◽  
Kabuki Syndrome ◽  
Rna Seq ◽  
Wide Range

AbstractCongenital Heart Defects (CHDs) are the most common form of birth defects, observed in 4-10/1000 live births. CHDs result in a wide range of structural and functional abnormalities of the heart which significantly affect quality of life and mortality. CHDs are often seen in patients with mutations in epigenetic regulators of gene expression, like the genes implicated in Kabuki syndrome – KMT2D and KDM6A, which play important roles in normal heart development and function. Here, we examined the role of two epigenetic histone modifying enzymes, KMT2D and KDM6A, in the expression of genes associated with early heart and neural crest cell (NCC) development. Using CRISPR/Cas9 mediated mutagenesis of kmt2d, kdm6a and kdm6al in zebrafish, we show cardiac and NCC gene expression is reduced, which correspond to affected cardiac morphology and reduced heart rates. To translate our results to a human pathophysiological context and compare transcriptomic targets of KMT2D and KDM6A across species, we performed RNA sequencing (seq) of lymphoblastoid cells from Kabuki Syndrome patients carrying mutations in KMT2D and KDM6A. We compared the human RNA-seq datasets with RNA-seq datasets obtained from mouse and zebrafish. Our comparative interspecies analysis revealed common targets of KMT2D and KDM6A, which are shared between species, and these target genes are reduced in expression in the zebrafish mutants. Taken together, our results show that KMT2D and KDM6A regulate common and unique genes across humans, mice, and zebrafish for early cardiac and overall development that can contribute to the understanding of epigenetic dysregulation in CHDs.

scholarly journals Advances in Cardiac Development and Regeneration Using Zebrafish as a Model System for High-Throughput Research

2021 ◽  
Vol 9 (4) ◽  
pp. 40
Author(s):  
Nicholas Francoeur ◽  
Rwik Sen
Keyword(s):  
Heart Disease ◽  
Heart Development ◽  
Molecular Mechanisms ◽  
Developmental Stages ◽  
Cardiac Development ◽  
Model Organism ◽  
The United States ◽  
Therapeutic Interventions ◽  
Chip Sequencing ◽  
Active Transcription

Heart disease is the leading cause of death in the United States and worldwide. Understanding the molecular mechanisms of cardiac development and regeneration will improve diagnostic and therapeutic interventions against heart disease. In this direction, zebrafish is an excellent model because several processes of zebrafish heart development are largely conserved in humans, and zebrafish has several advantages as a model organism. Zebrafish transcriptomic profiles undergo alterations during different stages of cardiac development and regeneration which are revealed by RNA-sequencing. ChIP-sequencing has detected genome-wide occupancy of histone post-translational modifications that epigenetically regulate gene expression and identified a locus with enhancer-like characteristics. ATAC-sequencing has identified active enhancers in cardiac progenitor cells during early developmental stages which overlap with occupancy of histone modifications of active transcription as determined by ChIP-sequencing. CRISPR-mediated editing of the zebrafish genome shows how chromatin modifiers and DNA-binding proteins regulate heart development, in association with crucial signaling pathways. Hence, more studies in this direction are essential to improve human health because they answer fundamental questions on cardiac development and regeneration, their differences, and why zebrafish hearts regenerate upon injury, unlike humans. This review focuses on some of the latest studies using state-of-the-art technology enabled by the elegant yet simple zebrafish.

The role of the neural crest in cardiac development

2018 ◽  
Author(s):  
Laura A. Dyer ◽  
Margaret L. Kirby
Keyword(s):  
Neural Crest ◽  
Neural Tube ◽  
Heart Development ◽  
Cardiac Development ◽  
Signalling Pathways ◽  
Pharyngeal Arches ◽  
Cardiac Neural Crest ◽  
Final Destination ◽  
Dorsal Neural Tube

The cardiac neural crest (CNC) plays pivotal roles in numerous steps of cardiac development. Every aspect of the CNC cell’s lifespan is highly orchestrated, from its induction in the dorsal neural tube to its migration to its differentiation at its final destination. During migration, CNC cells are affected by their environment and simultaneously modulate the extra-cellular milieu through which they migrate. In the pharyngeal arches, CNC cells repattern the originally symmetrical arch arteries, producing the great arteries. Because the cardiac neural crest is essential for many aspects of heart development, it is unsurprising that human CNC-related syndromes have severe phenotypes. This chapter describes how CNC cells are formed and contribute to their final destinations. Essential signalling pathways are presented in the context of CNC development, and CNC-related syndromes are included to highlight this population’s broad importance during development.

scholarly journals Salome Gluecksohn-Waelsch. 6 October 1907—7 November 2007

2019 ◽  
Vol 67 ◽  
pp. 153-171
Author(s):  
Virginia E. Papaioannou
Keyword(s):  
New York ◽  
Molecular Biology ◽  
Model Organism ◽  
Albert Einstein College ◽  
Albert Einstein ◽  
Developmental Genetics ◽  
Developmental Studies ◽  
Columbia University ◽  
Professional Career

Salome Gluecksohn-Waelsch was a pioneer in establishing the field of mammalian developmental genetics, bringing together experimental embryology and genetics at a time when the role of genes in development was far from accepted. She studied in Germany in the 1930s with the renowned experimental embryologist Hans Spemann and then moved to New York City where she spent her entire professional career at Columbia University and the Albert Einstein College of Medicine of Yeshiva University. Her career was remarkable not only for its longevity—she continued experiments well into her 90s—but also for ushering in new ways of approaching developmental biology in mammals. In her studies of the T -complex in mice, she made use of naturally occurring mutations as nature's own experiments that allowed the investigation of the normal role of the genes in the events of morphogenesis. In her later work with the albino chromosomal deletions, she extended her studies to the genetics of physiological traits. Throughout the decades that saw a blossoming of the entire field of genetics, Salome Gluecksohn-Waelsch's work tackling some of the most perplexing problems in mammalian genetics firmly established the mouse as model organism, not only for studying development, but also for the eventual application of molecular biology techniques to development. Her published work is a beautifully coherent and rigorous opus, for which she received many honours. Her influence on a generation of geneticists, developmental biologists and the field of developmental genetics was profound. The life of Salome Gluecksohn–Waelsch spanned a century that suffered the destructive upheaval of two world wars but also saw phenomenal progress in the sciences, including embryology and genetics. At the start of Salome's career, these two fields were far apart and developmental genetics was barely a concept. Along with a few other pioneers, Salome was instrumental in establishing that genes actually had roles in development and in founding the field of mammalian developmental genetics. Her career laid the ground work for the eventual integration of genetic and developmental studies through molecular biology. Salome Gluecksohn–Waelsch published under four different names at different stages of her life and career: Salome Glücksohn, Salome Gluecksohn–Schoenheimer, Salome Gluecksohn–Waelsch, and Salome G. Waelsch. Among her colleagues and friends, she was almost universally known as Salome and so for the purpose of this biographical memoir, I have chosen to refer to her by her first name, out of friendship and respect.

scholarly journals Phosphodiesterases Expression during Murine Cardiac Development

2021 ◽  
Vol 22 (5) ◽  
pp. 2593
Author(s):  
Thays Maria da Conceição Silva Carvalho ◽  
Silvia Cardarelli ◽  
Mauro Giorgi ◽  
Andrea Lenzi ◽  
Andrea M. Isidori ◽  
...  
Keyword(s):  
Heart Development ◽  
Fetal Heart ◽  
Cardiac Development ◽  
Large Family ◽  
Hydrolytic Activity ◽  
Development Data ◽  
Heart Formation ◽  
Camp And Cgmp ◽  
Developing Mice

3′-5′ cyclic nucleotide phosphodiesterases (PDEs) are a large family of enzymes playing a fundamental role in the control of intracellular levels of cAMP and cGMP. Emerging evidence suggested an important role of phosphodiesterases in heart formation, but little is known about the expression of phosphodiesterases during cardiac development. In the present study, the pattern of expression and enzymatic activity of phosphodiesterases was investigated at different stages of heart formation. C57BL/6 mice were mated and embryos were collected from 14.5 to 18.5 days of development. Data obtained by qRT-PCR and Western blot analysis showed that seven different isoforms are expressed during heart development, and PDE1C, PDE2A, PDE4D, PDE5A and PDE8A are modulated from E14.5 to E18.5. In heart homogenates, the total cAMP and cGMP hydrolytic activity is constant at the evaluated times, and PDE4 accounts for the majority of the cAMP hydrolyzing ability and PDE2A accounts for cGMP hydrolysis. This study showed that a subset of PDEs is expressed in developing mice heart and some of them are modulated to maintain constant nucleotide phosphodiesterase activity in embryonic and fetal heart.

scholarly journals β-Catenin–dependent mechanotransduction dates back to the common ancestor of Cnidaria and Bilateria

2018 ◽  
Vol 115 (24) ◽  
pp. 6231-6236 ◽  
Author(s):  
Ekaterina Pukhlyakova ◽  
Andrew J. Aman ◽  
Kareem Elsayad ◽  
Ulrich Technau
Keyword(s):  
Gene Expression ◽  
Common Ancestor ◽  
Marker Gene ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Model Organism ◽  
The Common ◽  
Gene Regulatory ◽  
Ancient Gene

Although the genetic regulation of cellular differentiation processes is well established, recent studies have revealed the role of mechanotransduction on a variety of biological processes, including regulation of gene expression. However, it remains unclear how universal and widespread mechanotransduction is in embryonic development of animals. Here, we investigate mechanosensitive gene expression during gastrulation of the starlet sea anemone Nematostella vectensis, a cnidarian model organism. We show that the blastoporal marker gene brachyury is down-regulated by blocking myosin II-dependent gastrulation movements. Brachyury expression can be restored by applying external mechanical force. Using CRISPR/Cas9 and morpholino antisense technology, we also show that mechanotransduction leading to brachyury expression is β-catenin dependent, similar to recent findings in fish and Drosophila [Brunet T, et al. (2013) Nat Commun 4:1–15]. Finally, we demonstrate that prolonged application of mechanical stress on the embryo leads to ectopic brachyury expression. Thus, our data indicate that β-catenin–dependent mechanotransduction is an ancient gene regulatory mechanism, which was present in the common ancestor of cnidarians and bilaterians, at least 600 million years ago.

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