Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2008 Oct-Nov;98(2-3):301-8.
doi: 10.1016/j.pbiomolbio.2009.01.011. Epub 2009 Jan 31.

Zebrafish genetic models for arrhythmia

David J Milan  1 , Calum A Macrae
Affiliations
Review

Zebrafish genetic models for arrhythmia

David J Milan et al. Prog Biophys Mol Biol. 2008 Oct-Nov.

Abstract

Over the last decade the zebrafish has emerged as a major genetic model organism. While stimulated originally by the utility of its transparent embryos for the study of vertebrate organogenesis, the success of the zebrafish was consolidated through multiple genetic screens, sequencing of the fish genome by the Sanger Center, and the advent of extensive genomic resources. In the last few years the potential of the zebrafish for in vivo cell biology, physiology, disease modeling and drug discovery has begun to be realized. This review will highlight work on cardiac electrophysiology, emphasizing the arenas in which the zebrafish complements other in vivo and in vitro models; developmental physiology, large-scale screens, high-throughput disease modeling and drug discovery. Much of this work is at an early stage, and so the focus will be on the general principles, the specific advantages of the zebrafish and on future potential.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Phenotyping is straightforward as zebrafish larvae are transparent (a), Phenotype at 48 hpf of an embryo injected with mismatch control oligo compared with a morphant (injected with 25 ng of morpholino dsc2) embryo at the same stage (b). High-resolution pictures of the heart of morphant embryo (c) compared to control-injected embryo (d). Transmission electron microscopy of cardiac desmosomes from a control embryo (e) and morphant embryo (f) at 48 hpf.
Figure 2
Figure 2
Transgenic fluorescent reporters In this figure a transgenic construct with a fluorescent reporter downstream of a hypertrophy responsive promoter enable direct in vivo assessment of physiologic pathways. This approach can readily be adapted to automated screening.
Figure 3
Figure 3
Zebrafish can be maintained in multiwell plates The size of the zebrafish enables several embryos to survive for days in the wells of 96 or 384 well plates. Combining this with automated phenotyping allows directed genetic or chemical screens of a scale similar to those undertaken in invertebrate model organisms, yet for vertebrate traits
Figure 4
Figure 4
Staged screening By combining different assays of varying throughput and resolution with the genetic tools available for the zebrafish, it is possible to optimize assays for both sensitivity and specificity. In this example, a highly sensitive (but relatively non-specific) first round assay (heart rate and AV block), which can be completely automated, is combined in series with high-resolution second round assays (calcium and voltage imaging), which offer markedly higher specificity. Together with known disease mutants and functional genomics approaches these can be used to develop a screening tool for drug-induced repolarization toxicity or in discovery mode for pharmacogenetic gene identification.
Figure 5
Figure 5
Repolarization network identified by zebrafish screening Interactions between known repolarization genes (blue symbols) and the genes identified in a phenotype driven screen are depicted. Single lines indicate genetic interactions supported by data from multiple model organisms. Bold lines show direct physical interactions. A dashed line represents a physical interaction that may not be direct. The arrow represents a downstream regulatory effect, the mechanism of which is unknown.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Amatruda JF, Shepard JL, Stern HM, Zon LI. Zebrafish as a cancer model system. Cancer Cell. 2002;1(3):229–31. - PubMed
    1. Amsterdam A, Burgess S, Golling G, Chen W, Sun Z, Townsend K, Farrington S, Haldi M, Hopkins N. A large-scale insertional mutagenesis screen in zebrafish. Genes Dev. 1999;13(20):2713–24. - PMC - PubMed
    1. Anderson KV, Ingham PW. The transformation of the model organism: a decade of developmental genetics. Nat Genet. 2003;33(Suppl):285–93. - PubMed
    1. Arnaout R, Ferrer T, Huisken J, Spitzer K, Stainier DY, Tristani-Firouzi M, Chi NC. Zebrafish model for human long QT syndrome. Proc Natl Acad Sci U S A. 2007;104(27):11316–21. - PMC - PubMed
    1. Asakawa K, Suster ML, Mizusawa K, Nagayoshi S, Kotani T, Urasaki A, Kishimoto Y, Hibi M, Kawakami K. Genetic dissection of neural circuits by Tol2 transposon-mediated Gal4 gene and enhancer trapping in zebrafish. Proc Natl Acad Sci U S A. 2008;105(4):1255–60. - PMC - PubMed

Substances