title: Conditional Gata2 inactivation results in HSC loss and lymphatic mispatterning.
abstract: The transcription factor GATA-2 plays vital roles in quite diverse developmental programs, including hematopoietic stem cell (HSC) survival and proliferation. We previously identified a vascular endothelial (VE) enhancer that regulates GATA-2 activity in pan-endothelial cells. To more thoroughly define the in vivo regulatory properties of this enhancer, we generated a tamoxifen-inducible Cre transgenic mouse line using the Gata2 VE enhancer (Gata2 VECre) and utilized it to temporally direct tissue-specific conditional loss of Gata2. Here, we report that Gata2 VECre-mediated loss of GATA-2 led to anemia, hemorrhage, and eventual death in edematous embryos. We further determined that the etiology of anemia in conditional Gata2 mutant embryos involved HSC loss in the fetal liver, as demonstrated by in vitro colony-forming and immunophenotypic as well as in vivo long-term competitive repopulation experiments. We further documented that the edema and hemorrhage in conditional Gata2 mutant embryos were due to defective lymphatic development. Thus, we unexpectedly discovered that in addition to its contribution to endothelial cell development, the VE enhancer also regulates GATA-2 expression in definitive fetal liver and adult BM HSCs, and that GATA-2 function is required for proper lymphatic vascular development during embryogenesis.
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
authors.forename: Kim-Chew
authors.initials: KC
authors.lastname: Lim
authors.forename: Tomonori
authors.initials: T
authors.lastname: Hosoya
authors.forename: William
authors.initials: W
authors.lastname: Brandt
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Ku
authors.forename: Sakie
authors.initials: S
authors.lastname: Hosoya-Ohmura
authors.forename: Sally A
authors.initials: SA
authors.lastname: Camper
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: James Douglas
authors.initials: JD
authors.lastname: Engel
mesh_terms: D000740:Anemia / Q000196:embryology / Q000235:genetics*; D000818:Animals; D002455:Cell Division; D002470:Cell Survival; D003114:Colony-Forming Units Assay; D004742:Enhancer Elements, Genetic; D005260:Female; D005313:Fetal Death / Q000235:genetics*; D050989:GATA2 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017930:Genes, Reporter; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006470:Hemorrhage / Q000196:embryology / Q000235:genetics*; D016130:Immunophenotyping; D008099:Liver / Q000166:cytology / Q000196:embryology; D008208:Lymphatic System / Q000196:embryology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity; D011247:Pregnancy; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D013629:Tamoxifen