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  • Review Article
  • Published:

Animal models of human disease: zebrafish swim into view

Nature Reviews Genetics volume 8, pages 353–367 (2007)Cite this article

Key Points

  • Zebrafish have long contributed to biological and medical research, especially as a model for developmental and toxicological studies.

  • Particularly useful attributes of zebrafish include: ex vivo fertilization and embryogenesis; optical transparency of embryos and larvae; rapid embryological development; cheap housing costs; and genetic tractability.

  • Genetic techniques that have been developed for zebrafish make them an attractive vertebrate model for efficient, cost-effective, invertebrate-style forward genetics. Genetic resources include a genome-sequencing project that is nearing completion.

  • Large-scale chemical and insertional mutagenic screens have generated many zebrafish mutants with defects that are analogous to human genetic diseases, at the molecular and cellular-pathological levels.

  • Reverse-genetic techniques such as TILLING (_targeting induced local lesions in genomes) allow the recovery of zebrafish with mutant disease-gene alleles, overcoming the lack of a technique for gene _targeting by homologous recombination.

  • Transgenic zebrafish disease models with tissue-restricted disease-gene expression and fluorescently marked cell types enable disease mechanisms to be studied in vivo.

  • Zebrafish are proving to be good models of several acquired diseases including cancer, inflammation and infection.

  • Zebrafish are an emerging model for therapeutic drug discovery by 'chemical genetics', whereby chemical libraries are screened to find small molecules that suppress disease-related phenotypes.

Abstract

Despite the pre-eminence of the mouse in modelling human disease, several aspects of murine biology limit its routine use in large-scale genetic and therapeutic screening. Many researchers who are interested in an embryologically and genetically tractable disease model have now turned to zebrafish. Zebrafish biology allows ready access to all developmental stages, and the optical clarity of embryos and larvae allow real-time imaging of developing pathologies. Sophisticated mutagenesis and screening strategies on a large scale, and with an economy that is not possible in other vertebrate systems, have generated zebrafish models of a wide variety of human diseases. This Review surveys the achievements and potential of zebrafish for modelling human diseases and for drug discovery and development.

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Figure 1: Generating zebrafish disease models.
Figure 2: The application of chemical genetics in zebrafish.

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Acknowledgements

We thank W. Alexander, J. Horsfield, J. Heath, J. Postlethwait and R. Currie for their helpful comments on aspects of the manuscript. G.J.L. gratefully acknowledges the support of the Department of Clinical Haematology and Medical Oncology and the Bone Marrow Research Laboratories at the Royal Melbourne Hospital, Australia. G.J.L.'s work using zebrafish to model haematological disease is supported by the National Health and Medical Research Council (NHMRC, Australia) and the National Institutes of Health (NIH, USA). P.D.C's work on using zebrafish to model muscular dystrophy is supported by the Muscular Dystrophy Association (USA), the Human Frontier Science Program and NHMRC.

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Authors and Affiliations

  1. Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3050, Victoria, Australia

    Graham J. Lieschke

  2. Muscle Development Laboratory, The Victor Chang Cardiac Research Institute, 384 Victoria Street, Darlinghurst, Sydney, 2010, New South Wales, Australia

    Peter D. Currie

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  1. Graham J. Lieschke
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Correspondence to Graham J. Lieschke or Peter D. Currie.

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DATABASES

OMIM

Duchenne muscular dystrophy

FURTHER INFORMATION

Graham Lieschke's homepage

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Sanger Centre

The Danio rerio Sequencing Project

The Zebrafish Model Organism Database (ZFIN)

Trans-NIH Zebrafish Initiative

Zebrafish International Resource Center

ZF-MODELS: Zebrafish Models for Human Development and Disease

Znomics

Glossary

Shotgun and minimum tiling path sequencing

Two approaches to whole-genome sequencing. Shotgun sequencing refers to the random acquisition of sequence. Minimum tiling path sequencing refers to the collection of sequence in an ordered, directed manner, such as the systematic sequencing of an entire BAC clone from one end to the other.

Candidate gene approach

Characterizing mutants by focusing attention on individual genes that, based on some prior information, might plausibly underlie the mutant phenotype, as compared to a systematic positional cloning strategy.

Hepatoerythropoietic porphyria

A congenital syndrome that is characterized clinically by light-sensitive dermatitis and biochemically by high urinary uroporphyrin excretion, due to defects in the gene encoding uroporphyrinogen decarboxylase.

Erythropoietic protoporphyria

A congenital syndrome that results from overproduction of protopophyrin due to a defect in the haem-synthesis enzyme ferrochelatase. It is characterized by light-sensitive dermatitis, mild anaemia and occasionally liver dysfunction and neuropathy.

DiGeorge syndrome

A syndrome that combines craniofacial, aortic, cardiac, thymic and auditory developmental defects, many of which are attributable to haploinsufficiency of the TBX1 gene.

Congenital dyserythropoietic anaemia type 2

An hereditary anaemia characterized by binucleate marrow erythroid precursors, ineffective erythropoiesis, and acidified-serum-sensitive red cells (a positive Ham test). Although it maps to 20q11.2, the genetic basis is unknown.

Polycystic kidney diease

A genetically heterogenous group of disorders that are characterized by multiple renals cysts, associated with liver cysts and cerebral aneurysms.

Hermansky–Pudlak syndrome

A genetically heterogeneous syndrome that combines albinism, a bleeding diathesis and lysosomal storage defects with characteristic pigmented reticuloendothelial cells.

Familial dilated cardiomyopathy

A spectrum of familial cardiomyopathies, a subset of which have been associated with mutations of the TTN gene.

Prodromal disease phase

A phase of a disease in which a specific early symptom prefigures the full development of a disease, or a symptom indicates that a disease attack is imminent.

Conditioned place preference test

A psychological test to determine whether the regular association of a particular stimulus with a particular location leads to an alteration in behaviour that favours the location, regardless of whether the stimulus is present.

Caging

An experimental approach that delivers reagents in an inactive 'caged' form that can later be activated by a chemical, physical or genetic 'uncaging' event.

Spinal muscular atrophy

A collection of syndromes caused by mutations in the SMN1 gene, characterized by spinal motor neuron degeneration causing muscle weakness and wasting.

Congenital sideroblastic anaemia

A congenital anaemia that is morphologically characterized by marrow red cell precursors with aggregates of non-haem iron around their nuclei, which is detectable by Prussian blue staining.The condition results from mutations in the gene encoding the haeme-synthesis enzyme δ-aminolevulinate synthetase.

Mosaic eye assay

A genetic assay based on the identification of different genetically determined pigmentation phenotypes in adjacent retinal pigment epithelium cells.

Coarctation of the aorta

A disorder, usually congenital, resulting from a constriction in the thoracic aorta, typically in the vicinity of the ductus arteriosus. Upper-limb hypertension is a clinical characteristic.

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Lieschke, G., Currie, P. Animal models of human disease: zebrafish swim into view. Nat Rev Genet 8, 353–367 (2007). https://doi.org/10.1038/nrg2091

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