Zebrafish models in cardiac development and congenital heart birth defects

Department of Medicine, Division of Cardiology, University of California, San Diego, CA 92093-0613J, USA.
Differentiation (Impact Factor: 3.44). 06/2012; 84(1):4-16. DOI: 10.1016/j.diff.2012.05.005
Source: PubMed


The zebrafish has become an ideal vertebrate animal system for investigating cardiac development due to its genetic tractability, external fertilization, early optical clarity and ability to survive without a functional cardiovascular system during development. In particular, recent advances in imaging techniques and the creation of zebrafish transgenics now permit the in vivo analysis of the dynamic cellular events that transpire during cardiac morphogenesis. As a result, the combination of these salient features provides detailed insight as to how specific genes may influence cardiac development at the cellular level. In this review, we will highlight how the zebrafish has been utilized to elucidate not only the underlying mechanisms of cardiac development and human congenital heart diseases (CHDs), but also potential pathways that may modulate cardiac regeneration. Thus, we have organized this review based on the major categories of CHDs-structural heart, functional heart, and vascular/great vessel defects, and will conclude with how the zebrafish may be further used to contribute to our understanding of specific human CHDs in the future.

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    • "According to VonBaer (1828) (as cited by Moorman and Christoffels (2003)), it is the embryonic rather than the adult heart that should be compared since the common features of a vertebrate group appear early in development. In the last twenty years the zebrafish (Danio rerio) has emerged as a powerful and increasingly popular model to study cardiac development (Hu et al., 2000; Bakkers, 2011) and cardiac defects (Antkiewicz et al., 2005; Tu and Chi, 2012). Forward genetic screens have identified many novel regulatory mechanisms with essential roles in cardiogenic specification and Contents lists available at ScienceDirect journal homepage: "
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    ABSTRACT: Heart formation is a complex, dynamic and highly coordinated process of molecular, morphogenetic and functional factors with each interacting and contributing to formation of the mature organ. Cardiac abnormalities in early life can be lethal in mammals but not in the zebrafish embryo which has been widely used to study the developing heart. While early cardiac development in the zebrafish has been well characterized, functional changes during development and how these relate to architectural, cellular and molecular aspects of development have not been well described previously. To address this we have carefully characterised cardiac structure, function, cardiomyocyte proliferation and cardiac-specific gene expression between 48 and 120hpf in the zebrafish. We show that the zebrafish heart increases in volume and changes shape significantly between 48 and 72hpf accompanied by a 40% increase in cardiomyocyte number. Between 96 and 120hpf, while external heart expansion slows, there is rapid formation of a mature and extensive trabecular network within the ventricle chamber. While ejection fraction does not change during the course of development other determinants of contractile function increase significantly particularly between 72 and 96hpf leading to an increase in cardinal vein blood flow. This study has revealed a number of novel aspects of cardiac developmental dynamics with striking temporal orchestration of structure and function within the first few days of development. These changes are associated with changes in expression of developmental and maturational genes. This study provides important insights into the complex temporal relationship between structure and function of the developing zebrafish heart. Copyright © 2015 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.
    Differentiation 06/2015; 89(5). DOI:10.1016/j.diff.2015.05.001 · 3.44 Impact Factor
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    • "The embryos shown in d and h are strongly malformed: In d, the pharyngeal skeleton is completely absent, and the neurocranium is also strongly deformed, but still detectable (e ethmoid plate; t compressed trabeculae cranii). In h, parts of the pharyngeal skeleton are visible, but all elements were categorized severity 3 (from Strecker et al. 2013) Likewise, the zebrafish embryo model is being extensively explored with respect to cardiac and vascular disorders (Asnani & Peterson 2014, Bakkers 2011, Miura & Yelon 2011, Staudt & Stainier 2012, Tu & Chi 2012, Wilkinson et al. 2014), neurotoxicity (de Esch et al. 2012, Ho et al. 2013, Selderslaghs et al. 2010, 2013, Sipes et al. 2011, Tierney et al. 2010, 2011), endocrine disruption (Ankley et al. 2009, Scholz & Mayer 2008, Scholz et al. 2008, Segner 2009), and genotoxicity research (Scholz et al. 2008). "
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    ABSTRACT: Originally designed as an alternative for the acute fish toxicity test according to, e.g., OECD TG 203, the fish embryo test (FET) with the zebrafish (Danio rerio) has been optimized, standardized, and validated during an OECD validation study and adopted as OECD TG 236 as a test to assess toxicity of embryonic forms of fish. Given its excellent correlation with the acute fish toxicity test and the fact that non-feeding developmental stages of fish are not categorized as protected stages according to the new European Directive 2010/63/EU on the protection of animals used for scientific purposes, the FET is ready for use not only for range-finding but also as a true alternative for the acute fish toxicity test, as required for a multitude of national and international regulations. If-for ethical reasons-not accepted as a full alternative, the FET represents at least a refinement in the sense of the 3Rs principle. Objections to the use of the FET have mainly been based on the putative lack of biotransformation capacity and the assumption that highly lipophilic and/or high molecular weight substances might not have access to the embryo due to the protective role of the chorion. With respect to bioactivation, the only substance identified so far as not being activated in the zebrafish embryo is allyl alcohol; all other biotransformation processes that have been studied in more detail so far were found to be present, albeit, in some cases, at lower levels than in adult fish. With respect to larger molecules, the extension of the test duration to 96 h (i.e., beyond hatch) has-at least for the substances tested so far-compensated for the reduced access to the embryo; however, more research is necessary to fully explore the applicability of the FET to substances with a molecular weight >3 kDa as well as substances with a neurotoxic mode of action. An extension of the endpoints to also cover sublethal endpoints makes the FET a powerful tool for the detection of teratogenicity, dioxin-like activity, genotoxicity and mutagenicity, neurotoxicity, as well as various forms of endocrine disruption.
    Environmental Science and Pollution Research 11/2014; DOI:10.1007/s11356-014-3814-7 · 2.83 Impact Factor
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    • "We charted the spatial and temporal development of the voltage and Ca2+ patterns at 36, 54, and 102 hpf, using new fish at each time point (Figure 4). The heart showed distinct atrial and ventricular AP waveforms as early as 36 hpf (Figure 4A), though the wave propagation was peristaltic with neither a clear electrical nor morphological boundary between the chambers (Tu and Chi, 2012). The electrical APs recorded optically in vivo were similar to previous reports of patch clamp measurements on explanted hearts (Chi et al., 2008; Nemtsas et al., 2010). "
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    ABSTRACT: The cardiac action potential (AP) and the consequent cytosolic Ca(2+) transient are key indicators of cardiac function. Natural developmental processes, as well as many drugs and pathologies change the waveform, propagation, or variability (between cells or over time) of these parameters. Here we apply a genetically encoded dual-function calcium and voltage reporter (CaViar) to study the development of the zebrafish heart in vivo between 1.5 and 4 days post fertilization (dpf). We developed a high-sensitivity spinning disk confocal microscope and associated software for simultaneous three-dimensional optical mapping of voltage and calcium. We produced a transgenic zebrafish line expressing CaViar under control of the heart-specific cmlc2 promoter, and applied ion channel blockers at a series of developmental stages to map the maturation of the action potential in vivo. Early in development, the AP initiated via a calcium current through L-type calcium channels. Between 90 and 102 h post fertilization (hpf), the ventricular AP switched to a sodium-driven upswing, while the atrial AP remained calcium driven. In the adult zebrafish heart, a sodium current drives the AP in both the atrium and ventricle. Simultaneous voltage and calcium imaging with genetically encoded reporters provides a new approach for monitoring cardiac development, and the effects of drugs on cardiac function.
    Frontiers in Physiology 09/2014; 5:344. DOI:10.3389/fphys.2014.00344 · 3.53 Impact Factor
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