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  • Review Article
  • Published:

The zebrafish: a new model of T-cell and thymic development

Nature Reviews Immunology volume 5, pages 307–317 (2005)Cite this article

Key Points

  • Zebrafish have an adaptive immune system that comprises both T and B cells. The molecular pathways that regulate the development and maturation of these lymphoid-cell populations have been highly conserved throughout evolution.

  • The zebrafish is a powerful genetic model for dissecting the pathways that regulate erythrocyte and leukocyte development.

  • Genetic screens have identified mutations that perturb normal thymic and T-cell development, most of which result in severe cranio-facial defects. This indicates that many of these mutations affect pharyngeal-arch development and, subsequently, that the thymic anlage fails to form in mutated embryos.

  • Although the main advantage of using the zebrafish model system lies in the ability to carry out forward-genetic screens, the zebrafish model also offers many other advantages for studying thymic and T-cell development.

  • Transgenic zebrafish have been created that have green fluorescent protein (GFP)-labelled T cells, which allow the visualization of thymocyte development and function in a living organism. In conjunction with cell transplantation, transgenic approaches have provided unique reagents for the study of T-cell homing and the assessment of haematopoietic stem-cell function.

  • Reverse-genetic approaches rely on the targeted inactivation of gene products in developing organisms. Because gene-knockout technology has yet to be developed in zebrafish, researchers can use either targeting induced local lesions in genomes (TILLING) or morpholino antisense oligonucleotides to disrupt gene function in developing embryos.

  • TILLING is a technique that uses N-ethyl-N-nitrosourea mutagenesis and the sequencing of genomic DNA to detect point mutations that are present in a gene of interest. This technology has been used successfully to disrupt recombination-activating gene 1 (rag1) gene function in zebrafish, which alters immune function in homozygous mutant individuals.

  • Morpholinos are chemically modified antisense oligonucleotides that can be microinjected into one-cell-stage embryos. Because of their long half-life, these molecules can disrupt gene function for up to 5 days.

  • The high-throughput sequencing of cDNA libraries in conjunction with whole-mount in situ hybridization has allowed researchers to carry out expression-based screens in zebrafish embryos, which provide new avenues for gene discovery.

  • Small-molecule-inhibitor screens have been used to identify water-soluble compounds that can be taken up by living zebrafish larvae and can restore mutant gene function in embryos. Because T-cell ablation can be monitored in rag2–GFP- and light-chain kinase (lck)–GFP-transgenic fish, and because dexamethasone treatment results in the loss of fluorescently labelled thymocytes, it might be possible to carry out small-molecule-inhibitor screens that are designed to identify drugs that selectively kill thymocytes, which might identify new immunosuppressive drugs.

Abstract

T-cell and thymic development are processes that have been highly conserved throughout vertebrate evolution. Mammals, birds, reptiles and fish share common molecular signalling pathways that regulate the development of the adaptive immune system. This Review article focuses on defining the similarities and differences between zebrafish and mammalian T-cell immunobiology, and it highlights the advantages of using the zebrafish as a genetic model to uncover mutations that affect T-cell and thymic development. Finally, we summarize the use of the zebrafish as a new model for assessing stem-cell function and for drug discovery.

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Figure 1: Transgenesis in zebrafish.
Figure 2: Cell-transplantation assays.
Figure 3: N-ethyl-N-nitrosourea-mutagenesis screens to identify recessive mutations affecting T-cell and thymic development: classical F3 screens versus F2 gynogenetic diploid screens.
Figure 4: Targeting induced local lesions in genomes in zebrafish.
Figure 5: Morpholino antisense technology.

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Acknowledgements

D.M.L. is the Edmond J. Safra Foundation–Irvington Institute Fellow. This work is supported by the National Institutes of Health (United States). L.I.Z. is also supported by the Howard Hughes Medical Institute (United States).

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Authors and Affiliations

  1. Stem Cell Program and Division of Hematology/ Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, 1 Blackfan Circle, Karp Building, Seventh floor, Boston, 02115-5713, Massachusetts, USA

    David M. Langenau & Leonard I. Zon

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  1. David M. Langenau
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  2. Leonard I. Zon
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Correspondence to Leonard I. Zon.

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Related links

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DATABASES

Entrez Gene

gata1

hey2

ikaros

lck

rag1

rag2

TBX1

OMIM

DiGeorge syndrome

T-cell acute lymphoblastic leukaemia

FURTHER INFORMATION

The Danio rerio Sequencing Project

The Zebrafish Information Network (ZFIN)

Glossary

GYNOGENETIC

A term describing the production of offspring that have only maternally inherited chromosomes.

ENU MUTAGENESIS

(N-ethyl-N-nitrosourea mutagenesis). Male fish are treated with ENU to induce point mutations in the spermatozoa and are then mated with female fish. The resulting progeny have heterozygous genetic lesions that are inherited from the father.

BACTERIAL ARTIFICIAL CHROMOSOME

(BAC). A DNA construct that is used for cloning large genomic fragments into bacteria, which usually comprises 100–300 kilobases of genomic DNA.

DIGEORGE SYNDROME

A rare congenital disease that often results in immune suppression, heart defects and cranio-facial defects. DiGeorge syndrome occurs because of a large deletion on chromosome 22, which results in the disruption of several genes from this genetic locus. Remarkably, the variation in symptoms might be related to the amount of genetic material that is lost by chromosomal deletion.

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Langenau, D., Zon, L. The zebrafish: a new model of T-cell and thymic development. Nat Rev Immunol 5, 307–317 (2005). https://doi.org/10.1038/nri1590

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