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The first international Monterotondo (Rome), Italy. conference that focused on this organism Acknowledgements Michael Ashburner is at the Department of The helpful comments of K. Matthews, S. Brown, N. Jenkins, was convened in 1990 (REF. 12). Sponsored by Genetics, University of Cambridge, Downing J. Eppig and M. Hrabe de Angelis are gratefully acknowledged. the US National Institutes of Health (NIH) Street, Cambridge CB2 3EH, UK. and National Science Foundation (NSF), Online links and hosted by the consortium of ‘Oregon Correspondence to N.R. zebrafish laboratories’,the gathering of ~40 e-mail: [email protected] FURTHER INFORMATION Gene Ontology: http://www.geneontolgy.org scientists from the United States and Europe doi:10.1038/nrg891 Michael Ashburner’s lab: 1. Ashburner, M. Europe must grant crucial funds for http://www.gen.cam.ac.uk/dept/ashburner.html sought to appraise the potential of research biological research. Nature 402, 12 (1999). Nadia Rosenthal’s lab: http://www.embl-monterotondo.it with this organism. Here, we retrace the aus- 2. Wang, W. B., Leopold, R. A., Nelson, D. R. & Freeman, Access to this interactive links box is free online. picious origins of the zebrafish field that were recognized at that meeting, and the subsequent innovations that transformed the zebrafish into a leading model organism. TIMELINE Our perspective is personal and therefore necessarily incomplete. We highlight the sequential contributions of individual scien- Headwaters of the zebrafish — tists and reflect on the shifting cultural views in the scientific community that both pro- emergence of a new model vertebrate pelled and retarded the ascent of this new model system. David Jonah Grunwald and Judith S. Eisen Fashioning a genetic system The ability to carry out classical forward The understanding of vertebrate The zebrafish, a robust tropical fish that has genetic analyses rendered the zebrafish development has advanced considerably long been a common feature in home unique among vertebrate model organisms in recent years, primarily due to the study aquariums, has recently attained a pre-emi- and still continues to be largely responsible of a few model organisms. The zebrafish, nent position in biomedical research. for its power as a tool for studying vertebrate the newest of these models, has risen to Zebrafish researchers have amassed some- biology. The idea of applying mutational prominence because both genetic and thing that was previously thought to be analysis to study zebrafish embryonic devel- experimental embryological methods can impossible in a vertebrate — a vast store- opment originated with George Streisinger be easily applied to this animal. The house of mutations selected only on the (FIG. 1), who began working with the fish in combination of approaches has proven basis of how they affect the living organism. the late 1960s. Streisinger had been among powerful, yielding insights into the Hundreds of mutations that perturb basic the principal contributors to the dawn of the formation and function of individual developmental processes have been modern era of molecular genetics. Having tissues, organ systems and neural described, including those that affect the trained with Salvatore Luria and Max networks, and into human disease establishment of the shape of the embryo, Delbrück, Streisinger was at the core of the mechanisms. Here, we provide a personal the generation of germ layers, complex historic phage group throughout the 1950s, perspective on the history of zebrafish organ systems and specific cell types, the working at Caltech, Cold Spring Harbor, and research, from the assembly of the first organization of distinct brain regions Cambridge, UK. Streisinger’s phage work genetic and embryological tools through to and vascular architecture, and the establish- showed that the genetic code deduced in sequencing of the genome. ment of defined neural circuits1–4.The vitro coincided with the code in vivo, and NATURE REVIEWS | GENETICS VOLUME 3 | SEPTEMBER 2002 | 717 © 2002 Nature Publishing Group PERSPECTIVES Timeline | Landmarks in zebrafish research Late 1990s to early 2000s Mutations are cloned and several genes that The method for affect common Streisinger producing clonal processes are woven produces haploid lines of homozygous into molecular pathways. Late 1960s embryos from zebrafish is 1993 The Trans-NIH Zebrafish Streisinger eggs activated published. Systematic large-scale Initiative is launched. obtains with ultraviolet- Gynogenetic screens for embryonic- The results of the ‘Big Establishment of a The beginning zebrafish from irradiated, procedures and their lethal mutations begin in Screen’ are published in a centralized, web-based of whole- commercial genetically potential applications Tübingen, Germany, and single issue of database, ZFIN, and a genome suppliers. impotent sperm. are described. Boston, USA. Development, volume 123. stock centre, ZIRC. sequencing 1960 1970 1972 1980 1981 1988 1990 1993 1994 1996 1997 1998 2000 Mid-1970s Mid-1980s The first The first conference on The First Cold Mid-to-late 1990s one-eyed Homozygous diploid Establishment of a research description of zebrafish is convened in Spring Harbor Development of pinhead is the embryos derived only from community focused on an induced Eugene, Oregon. The Conference on linkage map and first mutation the maternal genome are developmental and genetic embryonic-lethal fate map of the zebrafish Zebrafish Genetics genomic to be used to reveal recessive studies with the zebrafish. mutation in the gastrula reveals that and Development resources. positionally mutations present in the Cell-lineage studies in the zebrafish is organization of the early is held. Three Insertional cloned. germ line of a female. early embryo, visualization published. zebrafish embryo is simi- hundred and fifty mutagenesis is Gynogenetic procedures of neurite outgrowth in a lar to that of other verte- international established and are developed for living zebrafish embryo, and brates. Cell transplanta- researchers attend large-scale tion to generate geneti- mapping and gene- mutagenesis and mapping — the zebrafish is screens for cally mosaic embryos is linkage studies. regimes are reported. no longer just a insertional used to test autonomy promising model. mutants begin. of gene function. no tail is the first mutation to be identified molecularly, using a candidate-gene approach. yielded insights into the molecular nature of Then, as today, the workings of the nervous ticular target sites”(G. Streisinger, 1974 supple- induced mutations and the genetic structure