Despite the pre-eminence of the mouse in modelling human disease, several aspects of murine biology limit its routine use in large-scale genetic and therapeutic screening. Many researchers who are interested in an embryologically and genetically tractable disease model have now turned to zebrafish. Zebrafish biology allows ready access to all developmental stages, and the optical clarity of embryos and larvae allow real-time imaging of developing pathologies. Sophisticated mutagenesis and screening strategies on a large scale, and with an economy that is not possible in other vertebrate systems, have generated zebrafish models of a wide variety of human diseases. This Review surveys the achievements and potential of zebrafish for modelling human diseases and for drug discovery and development.

Macrophages and neutrophils play important roles during the innate immune response, phagocytosing invading microbes and delivering antimicrobial compounds to the site of injury. Functional analyses of the cellular innate immune response in zebrafish infection/ inflammation models have been aided by transgenic lines with fluorophore-marked neutrophils. However, it has not been possible to study macrophage behaviors and neutrophil/macrophage interactions in vivo directly because there has been no macrophage-only reporter line. To remove this roadblock, a macrophagespecific marker was identified (mpeg1) and its promoter used in mpeg1-driven transgenes. mpeg1-driven transgenes are expressed in macrophage-lineage cells that do not express neutrophil-marking transgenes. Using these lines, the different dynamic behaviors of neutrophils and macrophages after wounding were compared side-by-side in compound transgenics. Macrophage/neutrophil interactions, such as phagocytosis of senescent neutrophils, were readily observed in real time. These zebrafish transgenes provide a new resource that will contribute to the fields of inflammation, infection, and leukocyte biology. (Blood. 2011;117(4): e49-e56)

Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of

The zebrafish is a useful model organism for developmental and genetic studies. The morphology and function of zebrafish myeloid cells were characterized. Adult zebrafish contain 2 distinct granulocytes, a heterophil and a rarer eosinophil, both of which circulate and are generated in the kidney, the adult hematopoietic organ. Heterophils show strong histochemical myeloperoxidasic activity, although weaker peroxidase activity was observed under some conditions in eosinophils and erythrocytes. Embryonic zebrafish have circulating immature heterophils by 48 hours after fertilization (hpf). A zebrafish myeloperoxidase homologue (myeloid-specific peroxidase; mpx) was isolated. Phylogenetic analysis suggested it represented a gene ancestral to the mammalian myeloperoxidase gene family. It IntroductionZebrafish (Danio rerio) have emerged as a useful model organism for studying a wide variety of physiological systems. Approximately 26 zebrafish mutants have genetic lesions primarily affecting hematopoiesis. Most of these were recognized on the basis of anemia 1,2 ; hence, it is not surprising that as the mutated genes underpinning these mutants were cloned, it was noted that they are genes primarily involved with erythropoiesis. Zebrafish mutants exist with lesions in genes encoding heme biosynthetic enzymes, 3-5 a structural protein, 6 and a novel iron transporter. 7 Another mutant has defective vasculogenetic and hematopoietic function, 8 suggesting a genetic lesion at the level of the embryonic hemangioblast. The study of early hematopoietic commitment and erythropoiesis in these mutants has generated a useful range of reagents. 9,10 Unlike erythropoiesis, which generates one mature cell type, myelopoiesis is a complex process that generates several cell types: monocytes-macrophages and several types of granulocytes. Teleosts, including cyprinids such as Danio, also have a process of multilineage myelopoiesis for host defense. 11 However, less is known about zebrafish myelopoiesis than about erythropoiesis.Macrophages have been recognized in zebrafish as early as the 13-somite stage (15 hours after fertilization [hpf]). They emerge from the anterior lateral plate mesoderm, migrate over the yolk sac, phagocytose cell corpses, and clear bacteria from the circulation. 12 Two markers of early macrophage commitment were characterized: draculin, which had an expression pattern overlapping that of early markers of erythroid commitment and also marked the rostral population of mobile macrophages, and L-plastin, which marked an early macrophage population as it spread over the yolk sac and a dispersed axial population of cells presumed to be tissue macrophages. 12 A zebrafish homologue of c-fms, the receptor for colonystimulating factor-1, has been isolated. Zebrafish csf1r shows several differences from its murine counterpart: in zebrafish, csf1r is expressed in neural crest cells and in macrophages; unlike the murine osteopetrosis mutant lacking colony-stimulating factor-1, the zebrafish csf1r mutant panther does not ha...