The zebrafish (Brachydanio rerio ) is a small tropical freshwater fish that began to be used as a genetic model system in the early 1980s. The zebrafish shares numerous anatomical and genetic similarities with higher vertebrates, including humans, both in the general body plan and in specific organs. Close parallels exist in many aspects of early embryogenesis and in the anatomical and histological features of the brain, spinal cord, sensory systems, cardiovascular system, and other organs. Not infrequently, genetic defects in zebrafish resemble human disorders. Owing to these similarities, zebrafish genetics is being broadly applied to address both basic biological questions and to model human inherited diseases.
Useful Traits for Researchers
Several characteristics favor the choice of zebrafish for genetic research. First, zebrafish are easy to maintain in large numbers in a small laboratory space. Second, their generation time is relatively short: three months. Finally, females produce large clutches of offspring, about 50 to 100 a week. The zebrafish also presents advantages for embryological analysis: Its embryos develop externally, and are largely transparent for the first 36 hours of development.
The first proponents of the zebrafish model, George Streisinger and his colleagues at the University of Oregon, outlined its genetic characteristics and provided a thorough description of zebrafish embryogenesis. Zebrafish research entered a new phase when two groups, at the University of Tuebingen (Germany), and at Harvard Medical School, performed large-scale chemical mutagenesis experiments and isolated nearly 2,000 mutations that affect almost every aspect of embryonic development, from gastrulation to axonal pathfinding. Once the mutations were identified, they were studied to determine their developmental effects, after which their genetic and molecular nature was analyzed. These early genetic studies in zebrafish were limited by the lack of genomic resources, such as maps of the genome or genomic libraries, but these deficiencies were gradually eliminated during the late 1990s. Zebrafish research has entered a new phase since the completion of the genome project. This effort provided the sequence of the entire zebrafish genome and made cloning of zebrafish genes much more efficient.
Ongoing Research Involving Zebrafish
Zebrafish research continues at a fast pace. New rounds of mutation identification are in progress. To supplement chemical mutagenesis, retroviral vectors were developed as mutagenic agents and applied on a large scale. Tools to study the functions of individual genes, such as transgenics , were developed in parallel to mutant screening approaches. A technique that complements mutagenesis screens in zebrafish very well is known as gene knockdown. This approach uses modified antisense oligonucleotides to block the function of specific genes. These oligonuculeotides contain a substitution of the sugar ring in the nucleic acid backbone that makes them resistant to degradation by enzymes in living tissues. Gene knockdown is widely used to study mutant phenotypes of genes for which chemically induced mutations are not available.
The usefulness of the zebrafish as a model organism originates in its unique combination of genetic and embryological characteristics. Genetic approaches, such as mutagenesis screens, can be combined in zebrafish with other techniques, enabling researchers to study cell movements, cell birth dates, or interactions between cells in the living embryo. Although most of the zebrafish genetic research focuses on embryonic development, other problems, such as the genetic basis of circadian rhythms, cancer formation, neurodegenerative disorders, and drug addiction, are also being addressed.
see also DNA Libraries; Model Organisms; Mutagenesis; Transgenic Organisms: Ethical Issues.
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