title: Immune-related zinc finger gene ZFAT is an essential transcriptional regulator for hematopoietic differentiation in blood islands.
abstract: TAL1 plays pivotal roles in vascular and hematopoietic developments through the complex with LMO2 and GATA1. Hemangioblasts, which have a differentiation potential for both endothelial and hematopoietic lineages, arise in the primitive streak and migrate into the yolk sac to form blood islands, where primitive hematopoiesis occurs. ZFAT (a zinc-finger gene in autoimmune thyroid disease susceptibility region/an immune-related transcriptional regulator containing 18 C(2)H(2)-type zinc-finger domains and one AT-hook) was originally identified as an immune-related transcriptional regulator containing 18 C(2)H(2)-type zinc-finger domains and one AT-hook, and is highly conserved among species. ZFAT is thought to be a critical transcription factor involved in immune-regulation and apoptosis; however, developmental roles for ZFAT remain unknown. Here we show that Zfat-deficient (Zfat(-/-)) mice are embryonic-lethal, with impaired differentiation of hematopoietic progenitor cells in blood islands, where ZFAT is exactly expressed. Expression levels of Tal1, Lmo2, and Gata1 in Zfat(-/-) yolk sacs are much reduced compared with those of wild-type mice, and ChIP-PCR analysis revealed that ZFAT binds promoter regions for these genes in vivo. Furthermore, profound reduction in TAL1, LMO2, and GATA1 protein expressions are observed in Zfat(-/-) blood islands. Taken together, these results suggest that ZFAT is indispensable for mouse embryonic development and functions as a critical transcription factor for primitive hematopoiesis through direct-regulation of Tal1, Lmo2, and Gata1. Elucidation of ZFAT functions in hematopoiesis might lead to a better understanding of transcriptional networks in differentiation and cellular programs of hematopoietic lineage and provide useful information for applied medicine in stem cell therapy.
authors.affiliation: Department of Cell Biology, Faculty of Medicine, and Center for Advanced Molecular Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takashima
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fujimoto
authors.forename: Keiko
authors.initials: K
authors.lastname: Doi
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Hirose
authors.forename: Midori
authors.initials: M
authors.lastname: Koyanagi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okamura
authors.forename: Masahide
authors.initials: M
authors.lastname: Kuroki
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.forename: Senji
authors.initials: S
authors.lastname: Shirasawa
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation / Q000235:genetics*; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D015017:Yolk Sac / Q000098:blood supply; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C489366:Tal1 protein, mouse; C529571:ZFAT protein, mouse