Journal of Cardiovascular Development and Disease

Research

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Open AccessArticle

Cardiac-Restricted Expression of VCP/TER94 RNAi or Disease Alleles Perturbs Drosophila Heart Structure and Impairs Function

by Meera C. Viswanathan, Anna C. Blice-Baum, Tzu-Kang Sang and Anthony Cammarato

J. Cardiovasc. Dev. Dis. 2016, 3(2), 19; https://doi.org/10.3390/jcdd3020019 - 24 May 2016

Cited by 15 | Viewed by 5848

Abstract

Valosin-containing protein (VCP) is a highly conserved mechanoenzyme that helps maintain protein homeostasis in all cells and serves specialized functions in distinct cell types. In skeletal muscle, it is critical for myofibrillogenesis and atrophy. However, little is known about VCP’s role(s) in the [...] Read more.

Valosin-containing protein (VCP) is a highly conserved mechanoenzyme that helps maintain protein homeostasis in all cells and serves specialized functions in distinct cell types. In skeletal muscle, it is critical for myofibrillogenesis and atrophy. However, little is known about VCP’s role(s) in the heart. Its functional diversity is determined by differential binding of distinct cofactors/adapters, which is likely disrupted during disease. VCP mutations cause multisystem proteinopathy (MSP), a pleiotropic degenerative disorder that involves inclusion body myopathy. MSP patients display progressive muscle weakness. They also exhibit cardiomyopathy and die from cardiac and respiratory failure, which are consistent with critical myocardial roles for the enzyme. Nonetheless, efficient models to interrogate VCP in cardiac muscle remain underdeveloped and poorly studied. Here, we investigated the significance of VCP and mutant VCP in the Drosophila heart. Cardiac-restricted RNAi-mediated knockdown of TER94, the Drosophila VCP homolog, severely perturbed myofibrillar organization and heart function in adult flies. Furthermore, expression of MSP disease-causing alleles engendered cardiomyopathy in adults and structural defects in embryonic hearts. Drosophila may therefore serve as a valuable model for examining role(s) of VCP in cardiogenesis and for identifying novel heart-specific VCP interactions, which when disrupted via mutation, contribute to or elicit cardiac pathology. Full article

(This article belongs to the Special Issue Non-mammalian Animal Models to Study Heart Development and Disease)

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Open AccessFeature PaperArticle

Modeling GATAD1-Associated Dilated Cardiomyopathy in Adult Zebrafish

by Jingchun Yang, Sahrish Shah, Timothy M. Olson and Xiaolei Xu

J. Cardiovasc. Dev. Dis. 2016, 3(1), 6; https://doi.org/10.3390/jcdd3010006 - 26 Jan 2016

Cited by 9 | Viewed by 6727

Abstract

Animal models have played a critical role in validating human dilated cardiomyopathy (DCM) genes, particularly those that implicate novel mechanisms for heart failure. However, the disease phenotype may be delayed due to age-dependent penetrance. For this reason, we generated an adult zebrafish model, [...] Read more.

Animal models have played a critical role in validating human dilated cardiomyopathy (DCM) genes, particularly those that implicate novel mechanisms for heart failure. However, the disease phenotype may be delayed due to age-dependent penetrance. For this reason, we generated an adult zebrafish model, which is a simpler vertebrate model with higher throughput than rodents. Specifically, we studied the zebrafish homologue of GATAD1, a recently identified gene for adult-onset autosomal recessive DCM. We showed cardiac expression of gatad1 transcripts, by whole mount in situ hybridization in zebrafish embryos, and demonstrated nuclear and sarcomeric I-band subcellular localization of Gatad1 protein in cardiomyocytes, by injecting a Tol2 plasmid encoding fluorescently-tagged Gatad1. We next generated gatad1 knock-out fish lines by TALEN technology and a transgenic fish line that expresses the human DCM GATAD1-S102P mutation in cardiomyocytes. Under stress conditions, longitudinal studies uncovered heart failure (HF)-like phenotypes in stable KO mutants and a tendency toward HF phenotypes in transgenic lines. Based on these efforts of studying a gene-based inherited cardiomyopathy model, we discuss the strengths and bottlenecks of adult zebrafish as a new vertebrate model for assessing candidate cardiomyopathy genes. Full article

(This article belongs to the Special Issue Non-mammalian Animal Models to Study Heart Development and Disease)

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Review

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Open AccessReview

Ciona as a Simple Chordate Model for Heart Development and Regeneration

by Heather Evans Anderson and Lionel Christiaen

J. Cardiovasc. Dev. Dis. 2016, 3(3), 25; https://doi.org/10.3390/jcdd3030025 - 9 Aug 2016

Cited by 28 | Viewed by 7660

Abstract

Cardiac cell specification and the genetic determinants that govern this process are highly conserved among Chordates. Recent studies have established the importance of evolutionarily-conserved mechanisms in the study of congenital heart defects and disease, as well as cardiac regeneration. As a basal Chordate, [...] Read more.

Cardiac cell specification and the genetic determinants that govern this process are highly conserved among Chordates. Recent studies have established the importance of evolutionarily-conserved mechanisms in the study of congenital heart defects and disease, as well as cardiac regeneration. As a basal Chordate, the Ciona model system presents a simple scaffold that recapitulates the basic blueprint of cardiac development in Chordates. Here we will focus on the development and cellular structure of the heart of the ascidian Ciona as compared to other Chordates, principally vertebrates. Comparison of the Ciona model system to heart development in other Chordates presents great potential for dissecting the genetic mechanisms that underlie congenital heart defects and disease at the cellular level and might provide additional insight into potential pathways for therapeutic cardiac regeneration. Full article

(This article belongs to the Special Issue Non-mammalian Animal Models to Study Heart Development and Disease)

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Open AccessReview

A Matter of the Heart: The African Clawed Frog Xenopus as a Model for Studying Vertebrate Cardiogenesis and Congenital Heart Defects

by Annemarie Hempel and Michael Kühl

J. Cardiovasc. Dev. Dis. 2016, 3(2), 21; https://doi.org/10.3390/jcdd3020021 - 4 Jun 2016

Cited by 19 | Viewed by 9230

Abstract

The African clawed frog, Xenopus, is a valuable non-mammalian model organism to investigate vertebrate heart development and to explore the underlying molecular mechanisms of human congenital heart defects (CHDs). In this review, we outline the similarities between Xenopus and mammalian cardiogenesis, and provide [...] Read more.

The African clawed frog, Xenopus, is a valuable non-mammalian model organism to investigate vertebrate heart development and to explore the underlying molecular mechanisms of human congenital heart defects (CHDs). In this review, we outline the similarities between Xenopus and mammalian cardiogenesis, and provide an overview of well-studied cardiac genes in Xenopus, which have been associated with congenital heart conditions. Additionally, we highlight advantages of modeling candidate genes derived from genome wide association studies (GWAS) in Xenopus and discuss commonly used techniques. Full article

(This article belongs to the Special Issue Non-mammalian Animal Models to Study Heart Development and Disease)

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Open AccessReview

Genome-Wide Approaches to Drosophila Heart Development

by Manfred Frasch

J. Cardiovasc. Dev. Dis. 2016, 3(2), 20; https://doi.org/10.3390/jcdd3020020 - 27 May 2016

Cited by 7 | Viewed by 6390

Abstract

The development of the dorsal vessel in Drosophila is one of the first systems in which key mechanisms regulating cardiogenesis have been defined in great detail at the genetic and molecular level. Due to evolutionary conservation, these findings have also provided major inputs [...] Read more.

The development of the dorsal vessel in Drosophila is one of the first systems in which key mechanisms regulating cardiogenesis have been defined in great detail at the genetic and molecular level. Due to evolutionary conservation, these findings have also provided major inputs into studies of cardiogenesis in vertebrates. Many of the major components that control Drosophila cardiogenesis were discovered based on candidate gene approaches and their functions were defined by employing the outstanding genetic tools and molecular techniques available in this system. More recently, approaches have been taken that aim to interrogate the entire genome in order to identify novel components and describe genomic features that are pertinent to the regulation of heart development. Apart from classical forward genetic screens, the availability of the thoroughly annotated Drosophila genome sequence made new genome-wide approaches possible, which include the generation of massive numbers of RNA interference (RNAi) reagents that were used in forward genetic screens, as well as studies of the transcriptomes and proteomes of the developing heart under normal and experimentally manipulated conditions. Moreover, genome-wide chromatin immunoprecipitation experiments have been performed with the aim to define the full set of genomic binding sites of the major cardiogenic transcription factors, their relevant target genes, and a more complete picture of the regulatory network that drives cardiogenesis. This review will give an overview on these genome-wide approaches to Drosophila heart development and on computational analyses of the obtained information that ultimately aim to provide a description of this process at the systems level. Full article

(This article belongs to the Special Issue Non-mammalian Animal Models to Study Heart Development and Disease)

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Open AccessReview

Regulatory Networks that Direct the Development of Specialized Cell Types in the Drosophila Heart

by TyAnna L. Lovato and Richard M. Cripps

J. Cardiovasc. Dev. Dis. 2016, 3(2), 18; https://doi.org/10.3390/jcdd3020018 - 12 May 2016

Cited by 5 | Viewed by 5125

Abstract

The Drosophila cardiac tube was once thought to be a simple linear structure, however research over the past 15 years has revealed significant cellular and molecular complexity to this organ. Prior reviews have focused upon the gene regulatory networks responsible for the specification [...] Read more.

The Drosophila cardiac tube was once thought to be a simple linear structure, however research over the past 15 years has revealed significant cellular and molecular complexity to this organ. Prior reviews have focused upon the gene regulatory networks responsible for the specification of the cardiac field and the activation of cardiac muscle structural genes. Here we focus upon highlighting the existence, function, and development of unique cell types within the dorsal vessel, and discuss their correspondence to analogous structures in the vertebrate heart. Full article

(This article belongs to the Special Issue Non-mammalian Animal Models to Study Heart Development and Disease)

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Open AccessFeature PaperReview

On the Morphology of the Drosophila Heart

by Barbara Rotstein and Achim Paululat

J. Cardiovasc. Dev. Dis. 2016, 3(2), 15; https://doi.org/10.3390/jcdd3020015 - 12 Apr 2016

Cited by 60 | Viewed by 10567

Abstract

The circulatory system of Drosophila melanogaster represents an easily amenable genetic model whose analysis at different levels, i.e., from single molecules up to functional anatomy, has provided new insights into general aspects of cardiogenesis, heart physiology and cardiac aging, to name a [...] Read more.

The circulatory system of Drosophila melanogaster represents an easily amenable genetic model whose analysis at different levels, i.e., from single molecules up to functional anatomy, has provided new insights into general aspects of cardiogenesis, heart physiology and cardiac aging, to name a few examples. In recent years, the Drosophila heart has also attracted the attention of researchers in the field of biomedicine. This development is mainly due to the fact that several genes causing human heart disease are also present in Drosophila, where they play the same or similar roles in heart development, maintenance or physiology as their respective counterparts in humans. This review will attempt to briefly introduce the anatomy of the Drosophila circulatory system and then focus on the different cell types and non-cellular tissue that constitute the heart. Full article

(This article belongs to the Special Issue Non-mammalian Animal Models to Study Heart Development and Disease)

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Open AccessReview

Transcriptional Regulation of Heart Development in Zebrafish

by Fei Lu, Adam D. Langenbacher and Jau-Nian Chen

J. Cardiovasc. Dev. Dis. 2016, 3(2), 14; https://doi.org/10.3390/jcdd3020014 - 9 Apr 2016

Cited by 21 | Viewed by 10237

Abstract

Cardiac transcription factors orchestrate the complex cellular and molecular events required to produce a functioning heart. Misregulation of the cardiac transcription program leads to embryonic developmental defects and is associated with human congenital heart diseases. Recent studies have expanded our understanding of the [...] Read more.

Cardiac transcription factors orchestrate the complex cellular and molecular events required to produce a functioning heart. Misregulation of the cardiac transcription program leads to embryonic developmental defects and is associated with human congenital heart diseases. Recent studies have expanded our understanding of the regulation of cardiac gene expression at an additional layer, involving the coordination of epigenetic and transcriptional regulators. In this review, we highlight and discuss discoveries made possible by the genetic and embryological tools available in the zebrafish model organism, with a focus on the novel functions of cardiac transcription factors and epigenetic and transcriptional regulatory proteins during cardiogenesis. Full article

(This article belongs to the Special Issue Non-mammalian Animal Models to Study Heart Development and Disease)

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Open AccessReview

Advances in the Study of Heart Development and Disease Using Zebrafish

by Daniel R. Brown, Leigh Ann Samsa, Li Qian and Jiandong Liu

J. Cardiovasc. Dev. Dis. 2016, 3(2), 13; https://doi.org/10.3390/jcdd3020013 - 9 Apr 2016

Cited by 90 | Viewed by 20390

Abstract

Animal models of cardiovascular disease are key players in the translational medicine pipeline used to define the conserved genetic and molecular basis of disease. Congenital heart diseases (CHDs) are the most common type of human birth defect and feature structural abnormalities that arise [...] Read more.

Animal models of cardiovascular disease are key players in the translational medicine pipeline used to define the conserved genetic and molecular basis of disease. Congenital heart diseases (CHDs) are the most common type of human birth defect and feature structural abnormalities that arise during cardiac development and maturation. The zebrafish, Danio rerio, is a valuable vertebrate model organism, offering advantages over traditional mammalian models. These advantages include the rapid, stereotyped and external development of transparent embryos produced in large numbers from inexpensively housed adults, vast capacity for genetic manipulation, and amenability to high-throughput screening. With the help of modern genetics and a sequenced genome, zebrafish have led to insights in cardiovascular diseases ranging from CHDs to arrhythmia and cardiomyopathy. Here, we discuss the utility of zebrafish as a model system and summarize zebrafish cardiac morphogenesis with emphasis on parallels to human heart diseases. Additionally, we discuss the specific tools and experimental platforms utilized in the zebrafish model including forward screens, functional characterization of candidate genes, and high throughput applications. Full article

(This article belongs to the Special Issue Non-mammalian Animal Models to Study Heart Development and Disease)

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Open AccessFeature PaperReview

The Early Stages of Heart Development: Insights from Chicken Embryos

by Johannes G. Wittig and Andrea Münsterberg

J. Cardiovasc. Dev. Dis. 2016, 3(2), 12; https://doi.org/10.3390/jcdd3020012 - 5 Apr 2016

Cited by 40 | Viewed by 20856

Abstract

The heart is the first functioning organ in the developing embryo and a detailed understanding of the molecular and cellular mechanisms involved in its formation provides insights into congenital malformations affecting its function and therefore the survival of the organism. Because many developmental [...] Read more.

The heart is the first functioning organ in the developing embryo and a detailed understanding of the molecular and cellular mechanisms involved in its formation provides insights into congenital malformations affecting its function and therefore the survival of the organism. Because many developmental mechanisms are highly conserved, it is possible to extrapolate from observations made in invertebrate and vertebrate model organisms to humans. This review will highlight the contributions made through studying heart development in avian embryos, particularly the chicken. The major advantage of chick embryos is their accessibility for surgical manipulation and functional interference approaches, both gain- and loss-of-function. In addition to experiments performed in ovo, the dissection of tissues for ex vivo culture, genomic, or biochemical approaches is straightforward. Furthermore, embryos can be cultured for time-lapse imaging, which enables tracking of fluorescently labeled cells and detailed analysis of tissue morphogenesis. Owing to these features, investigations in chick embryos have led to important discoveries, often complementing genetic studies in mice and zebrafish. As well as including some historical aspects, we cover here some of the crucial advances made in understanding early heart development using the chicken model. Full article

(This article belongs to the Special Issue Non-mammalian Animal Models to Study Heart Development and Disease)

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Open AccessFeature PaperReview

Drosophila in the Heart of Understanding Cardiac Diseases: Modeling Channelopathies and Cardiomyopathies in the Fruitfly

by Ouarda Taghli-Lamallem, Emilie Plantié and Krzysztof Jagla

J. Cardiovasc. Dev. Dis. 2016, 3(1), 7; https://doi.org/10.3390/jcdd3010007 - 18 Feb 2016

Cited by 13 | Viewed by 8648

Abstract

Cardiovascular diseases and, among them, channelopathies and cardiomyopathies are a major cause of death worldwide. The molecular and genetic defects underlying these cardiac disorders are complex, leading to a large range of structural and functional heart phenotypes. Identification of molecular and functional mechanisms [...] Read more.

Cardiovascular diseases and, among them, channelopathies and cardiomyopathies are a major cause of death worldwide. The molecular and genetic defects underlying these cardiac disorders are complex, leading to a large range of structural and functional heart phenotypes. Identification of molecular and functional mechanisms disrupted by mutations causing channelopathies and cardiomyopathies is essential to understanding the link between an altered gene and clinical phenotype. The development of animal models has been proven to be efficient for functional studies in channelopathies and cardiomyopathies. In particular, the Drosophila model has been largely applied for deciphering the molecular and cellular pathways affected in these inherited cardiac disorders and for identifying their genetic modifiers. Here we review the utility and the main contributions of the fruitfly models for the better understanding of channelopathies and cardiomyopathies. We also discuss the investigated pathological mechanisms and the discoveries of evolutionarily conserved pathways which reinforce the value of Drosophila in modeling human cardiac diseases. Full article

(This article belongs to the Special Issue Non-mammalian Animal Models to Study Heart Development and Disease)

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