title: Conditional knockout mice demonstrate function of Klf5 as a myeloid transcription factor.
abstract: Krüppel-like factor 5 (Klf5) encodes a zinc-finger transcription factor and has been reported to be a direct target of C/EBPα, a master transcription factor critical for formation of granulocyte-macrophage progenitors (GMP) and leukemic GMP. Using an in vivo hematopoietic-specific gene ablation model, we demonstrate that loss of Klf5 function leads to a progressive increase in peripheral white blood cells, associated with increasing splenomegaly. Long-term hematopoietic stem cells (HSCs), short-term HSCs (ST-HSCs), and multipotent progenitors (MPPs) were all significantly reduced in Klf5(Δ/Δ) mice, and knockdown of KLF5 in human CD34(+) cells suppressed colony-forming potential. ST-HSCs, MPPs, and total numbers of committed progenitors were increased in the spleen of Klf5(Δ/Δ) mice, and reduced β1- and β2-integrin expression on hematopoietic progenitors suggests that increased splenic hematopoiesis results from increased stem and progenitor mobilization. Klf5(Δ/Δ) mice show a significant reduction in the fraction of Gr1(+)Mac1(+) cells (neutrophils) in peripheral blood and bone marrow and increased frequency of eosinophils in the peripheral blood, bone marrow, and lung. Thus, these studies demonstrate dual functions of Klf5 in regulating hematopoietic stem and progenitor proliferation and localization in the bone marrow, as well as lineage choice after GMP, promoting increased neutrophil output at the expense of eosinophil production.
authors.affiliation: Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; Division of Haematology, SA Pathology, Adelaide, SA, Australia; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia;
authors.forename: Nur Hezrin
authors.initials: NH
authors.lastname: Shahrin
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; Division of Haematology, SA Pathology, Adelaide, SA, Australia;
authors.forename: Sonya
authors.initials: S
authors.lastname: Diakiw
authors.affiliation: Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia;
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Dent
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia; School of Paediatrics & Reproductive Health and Robinson Institute, University of Adelaide, Adelaide, SA, Australia; and Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.
authors.forename: Anna L
authors.identifier: 0000-0002-9023-0138
authors.initials: AL
authors.lastname: Brown
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; Division of Haematology, SA Pathology, Adelaide, SA, Australia; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia; School of Paediatrics & Reproductive Health and Robinson Institute, University of Adelaide, Adelaide, SA, Australia; and.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: D'Andrea
mesh_terms: D000818:Animals; D018821:CD18 Antigens / Q000096:biosynthesis / Q000235:genetics; D004804:Eosinophils / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D055014:Granulocyte-Macrophage Progenitor Cells / Q000166:cytology / Q000378:metabolism*; D019012:Integrin beta1 / Q000096:biosynthesis / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism
chemical_list: D018821:CD18 Antigens; D019012:Integrin beta1; C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors