title: Irf8 regulates macrophage versus neutrophil fate during zebrafish primitive myelopoiesis.
abstract: In vertebrates, myeloid cells comprise polymorphonuclear and mononuclear lineages that arise from 2 successive waves of development: a transitory primitive wave giving rise to limited myeloid cells during embryonic stage and a definitive wave capable of producing myeloid cells throughout the fetal and adult life. One key unresolved question is what factors dictate polymorphonuclear versus mononuclear lineage fates during myelopoiesis. Here we show that during zebrafish embryogenesis interferon regulatory factor-8 (irf8) is expressed specifically in macrophages but not neutrophils. Suppression of Irf8 function in zebrafish causes a depletion of macrophages and an enhanced output of neutrophils but does not affect the overall number, proliferation, and survival of primitive myeloid cells. These data indicate that the skewed myeloid lineage development in Irf8 knockdown embryos results from a cell-fate switching. Such a conclusion is further supported by the observation showing that overexpression of Irf8 promotes macrophage formation at the expense of neutrophil development. Genetic epistasis analysis reveals that Irf8 acts downstream of Pu.1 but is insufficient to promote macrophage development in the absence of Pu.1. Our findings demonstrate that Irf8 is a critical determinant for neutrophil versus macrophage fate choice during zebrafish primitive myelopoiesis.
authors.affiliation: State Key Laboratory of Molecular Neuroscience, Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Hao
authors.initials: H
authors.lastname: Jin
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Shi
authors.forename: Zilong
authors.initials: Z
authors.lastname: Wen
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D004625:Embryo, Nonmammalian; D047108:Embryonic Development / Q000187:drug effects / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D038042:Myelopoiesis / Q000187:drug effects / Q000235:genetics*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D013997:Time Factors; D015027:Zebrafish / Q000196:embryology / Q000235:genetics* / Q000276:immunology*; D000099185:Interferon Regulatory Factor-8
chemical_list: D049452:Green Fluorescent Proteins; D018840:HSP70 Heat-Shock Proteins; D050835:Interferon Regulatory Factors; D016376:Oligonucleotides, Antisense; D000099185:Interferon Regulatory Factor-8; C485184:enhanced green fluorescent protein