Zebrafish Models to Study Stem Cells

Zebrafish as a Model Organism

Zebrafish are small tropical freshwater fish often utilized in biomedical research with many advantages for such use. For example, embryos are fertilized ex vivo and grow outside the mother, allowing easy visualization of development. Additionally, development occurs rapidly, taking only days to transition from fertilized egg to free-swimming larva. Moreover, hundreds of embryos can be produced from a single pair of adult zebra-fish. This attribute, combined with their small size, allows large numbers of zebrafish to be produced and housed in a small space, making large-scale projects more practical and affordable. In addition to physical attributes, zebrafish are a great tool for biomedical research as they share a great deal of genetic similarity to humans. Combined, these characteristics make zebrafish an ideal vertebrate model for discovery of new regulators of stem cells.

Large-Scale Screening in Zebrafish

Zebrafish are attractive models for performing large-scale screening projects to identify novel factors controlling stem cells. Two main types of screens are performed in zebrafish: genetic and chemical. Genetic screens work by introducing hundreds to thousands of random mutations into DNA. If the mutation is recessive and disrupts the function of the gene product, when a zebrafish carries two mutant copies of the gene, it displays abnormal traits. For example, a forward genetic screen was performed to identify genes essential for hematopoietic stem cell (HSC) formation. Mutants lack HSCs and all differentiated blood cells. The screen uncovered roles for ribosomal components, splicing machinery, and epigenetic modifiers in HSC emergence. Defects in all of these processes were later linked to a variety of human blood disorders, such as bone marrow failure syndromes and malignancies thought to initiate from aberrant stem cells.

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Studies of zebrafish embryonic development may help determine the underlying cause of common neural tube defects–such as spina bifida–which occur in about 1 in 1,000 newborn children. These “see through” embryos allow all internal development to be cl early observed from the outside. (National Institute of General Medical Sciences/Alexander Schler)

In addition to genetic screens, zebrafish are amenable to drug screens. For these screens, developing zebrafish are exposed to a library of chemicals and then assessed for defects. The compounds used in screening often affect known pathways; thus similar to genetic screens, chemical screens can provide insight into which factors are essential for stem cell development. Moreover, many available chemical libraries consist of FDA-approved drugs, thus small molecules identified in zebrafish screens have a high potential to move quickly into the clinic. For example, a zebrafish chemical screen published in 2007 identified an essential role for the prostaglandin E2 (PGE2) pathway in HSC formation and was later shown to expand mammalian HSCs ex vivo. A clinical trial is already under way to test PGE2-mediated expansion of HSCs for human cord blood transplantation.

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