Medaka — a Model Organism from the Far East
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REVIEWS MEDAKA — A MODEL ORGANISM FROM THE FAR EAST Joachim Wittbrodt*, Akihiro Shima‡ and Manfred Schartl§ Genome sequencing has yielded a plethora of new genes the function of which can be unravelled through comparative genomic approaches. Increasingly, developmental biologists are turning to fish as model genetic systems because they are amenable to studies of gene function. Zebrafish has already secured its place as a model vertebrate and now its Far Eastern cousin — medaka — is emerging as an important model fish, because of recent additions to the genetic toolkit available for this organism. Already, the popularity of medaka among developmental biologists has led to important insights into vertebrate development. ZOOGEOGRAPHY Medaka, Oryzias latipes, is a small, egg-laying freshwater reviewing medaka research at that time, it covered top- The discipline of biology that fish native to Asia that is found primarily in Japan, but ics ranging from systematics and ZOOGEOGRAPHY, to early deals with the geographical also in Korea and eastern China. Many colour prints, embryonic development and the genetic control of sex distribution of animals. known as Ukiyo-e, from the Edo period of the seven- differentiation2. Subsequent important advances in teenth to the nineteenth centuries, show that medaka, medaka research have included the establishment of which in Japanese means a tiny fish with big eyes, once inbred strains (reviewed in REF.8), the development of *Developmental Biology used to be an integral part of everyday life in Japan1. transgenesis protocols9 and the establishment of MULTI- Programme, The physiology, embryology and genetics of medaka LOCUS TESTER STRAINS10. The development of mutagenesis EMBL-Heidelberg, 2 10 Meyerhofstrasse 1, have been extensively studied for the past 100 years .It protocols in 1991 led to the first systematic mutagene- 11 69012 Heidelberg, Germany. was first described scientifically under the name of sis screens for developmental phenotypes and, in ‡Department of Integrated Poecilia latipes and appeared in the Fauna Japonica in combination with detailed descriptions of medaka Biosciences 102, Graduate 1850, which was written by Phillip Franz von Siebold — anatomy12–14, they have led to the characterization of School of Frontier Sciences, a physician, surgeon and naturalist3 (FIG. 1). In 1906, many mutant phenotypes that were recovered from and Department of 4 Biological Sciences, Jordan and Snyder renamed this species Oryzias latipes, these screens. Genomic resources, combined with a School of Science, a name that was chosen to reflect the preferred habitat detailed linkage map, have also facilitated cloning of the The University of Tokyo, of medaka — the rice (Oryza sativa) fields. This habitat genes that are responsible for these mutant pheno- 5-1-5 Kashiwanoha, also gave rise to the common English name of medaka types15–17, which shows the power and the potential of Kashiwa-City, Tokyo 277- 8562, Japan. — ricefish. medaka as a genetic model system. §Theodor-Boveri Institute Medaka was first used to show Mendelian inheri- Comparative studies of more distantly related ver- für Biowissenschaften, tance in vertebrates from 1913 onwards (REFS 5–7). tebrate species are essential if we are to identify the University of Würzburg, However, the systematic genetic analysis of medaka conserved, as well as the species-specific, genetic and Am Hubland, 97074 dates back to 1921, when it was the first vertebrate in molecular mechanisms that underlie development Würzburg, Germany. Correspondence to J.W. which the occurrence of crossing over between X and Y and evolution. Medaka and zebrafish are ideal for this e-mails: chromosomes was shown5. Subsequently, genetic stud- purpose, as both separated from their last common jochen.wittbrodt@embl- ies in medaka have focused on pigmentation and sex ancestor ~110 million years (Myr) ago (FIG. 2). This heidelberg.de; determination, as discussed in more detail below. evolutionary distance is reflected in many aspects of [email protected]; [email protected] The key reference for medaka as a genetic model sys- their biology, including early development and sex wuerzburg.de tem was published in 1975 — Medaka (Killifish): determination. Both fish models offer several advan- DOI: 10.1038/nrg704 Biology and Strains by Tokio Yamamoto2.As well as tages, and both combine the power of genetics with NATURE REVIEWS | GENETICS VOLUME 3 | JANUARY 2002 | 53 © 2001 Macmillan Magazines Ltd REVIEWS a very hardy and less susceptible to disease (BOX 1). Despite several large-scale mutagenesis screens in zebrafish, the number of mutations recovered that correspond to those that have been identified in mouse and human is still limited. This might be due, in part, to the additional gene duplications that have occurred in teleosts. Therefore, studies of medaka can complement those of zebrafish and will provide b important additional phenotypes (H. Kondoh, per- sonal communication) that will prove useful in mod- elling human diseases16. Medaka as a genetic resource Spontaneous and induced mutants. Early work on c medaka identified various spontaneous pigmentation mutants5. The first systematic screen for spontaneous mutants in medaka was carried out at Nagoya University in 1960. Thirteen spontaneous mutants were identified in an initial survey of natural popula- tions and of breeding stocks from local commercial breeders. By 1975, 37 spontaneous mutations had Figure 1 | Views on medaka. a | A hand-coloured lithograph been reported, and the mutant phenotypes ranged of a male, probably derived from the northern population of from abnormal pigmentation and body size to fin or medaka, from the first description of medaka that was 26 published in 1850 (REF.3). Males from the b | northern and scale morphology defects . By 1990, the number of c | southern inbred strains differ significantly in body shape and spontaneous mutations that had been identified had in pigmentation. Nevertheless, both strains can be interbred to risen to 76. All of the original mutants are still main- produce fully fertile hybrids. tained at the medaka stock centre at Nagoya University (BOX 2). Most mutants recovered from this screen were defective in pigmentation, but other experimental embryology and molecular biology. mutants — such as double anal fins (Da), which has a Their short generation time of 2–3 months is compa- mirror-image duplication of ventral body structures, rable with the mouse, but is considerably shorter than and pectoral fin-less (pl) — despite their severe mor- that of Xenopus laevis (3 years) or Xenopus tropicalis phological phenotypes27,28, were viable. (6 months). Furthermore, the synchronous extra-uter- For decades, medaka was an important test system ine development of many transparent eggs makes it for environmental research. It is widely used for car- easy to follow early developmental processes in both cinogenesis studies29 and for testing ENDOCRINE DISRUPTORS fish. Large-scale genetic screens for genes that are in ecotoxicology30–32. Medaka was tested for its suscep- involved in vertebrate development and pathogenesis tibility to physical and chemical mutagens, and it was are in progress in medaka and have been completed in in the course of these experiments that conditions for zebrafish11,14,18. Notably, the zebrafish screens have systematic mutagenesis were established10,33. These yielded some mutants with diseases that closely resem- conditions turned out to be useful for mutagenizing ble human genetic diseases, and therefore can serve as not only medaka but also zebrafish34. The key issue in models for them19–21. these environmental studies was the establishment of Whereas zebrafish and its features as an experi- the mutagenic potential of the substance under study; mental system are well known among biologists, little this was done by counting the number of mutations is known about the applications or advantages of that were induced at specific loci or the number of research on medaka outside Japan and the Far East22. dominant-lethal phenotypes that were recovered after Here, we review the potential of medaka as a genetic exposure to various mutagenic agents. More than 300 model system and emphasize its complementarity to viable alleles of the known pigmentation genes were MULTI-LOCUS TESTER STRAIN other vertebrate model systems in studies of develop- isolated in screens of multi-locus tester strains that Strain that is homozygous at 35 several recessive loci and is used mental biology and evolution. Like any model system, involved more than 3 million loci . New screens for to detect induced recessive zebrafish has its limitations as to the types of question developmental mutants were carried out recently11,14 mutations in the germ line; the that it can be used to address, the most prominent in parallel with the environmental screens, and eye higher the number of marker example being sex determination. So far, nothing is and brain phenotypes were recovered at a high rate, loci, the higher the detection efficiency. known about sex determination in zebrafish and, showing that a morphology-based screen was possible remarkably, none of the many markers of the in medaka11. Although some of the mutant pheno- ENDOCRINE DISRUPTOR zebrafish genetic map have been found to be sex types were partly reminiscent of those recovered from An exogenous substance that linked23–25. Conversely, medaka has clearly defined sex zebrafish screens, some, such as Da or koepke, changes endocrine