Dysregulation of granulocyte, erythrocyte, and NK cell lineages in Fli-1 gene-targeted mice.
Targeted disruption of the Friend leukemia integration 1 (Fli-1) proto-oncogene results in severe dysmegakaryopoiesis and embryonic lethality. We used morula-stage aggregation as a strategy to further clarify the hematopoietic defects of the Fli-1 gene-targeted mice. Analyses of lineage expression of Fli-1(+/-) and Fli-1(-/-) cells in the peripheral blood and bone marrow of chimeric mice consistently demonstrated reduced numbers of neutrophilic granulocytes and monocytes and increased numbers of natural killer (NK) cells. Transplantation studies using sorted Fli-1 mutant cells produced similar findings. Clonal culture studies of bone marrow cells revealed increased numbers of granulocytic and early erythroid progenitors in the Fli-1(+/-) cells. The sorted Fli-1(-/-) bone marrow cells revealed specific down-regulation of CCAAT/enhancer binding protein-alpha (C/EBPalpha) and C/EBPepsilon, and the receptors for granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF), consistent with their critical roles in granulopoiesis. Collectively, these observations suggest previously unknown physiologic roles for Fli-1 in granulocytic, erythroid, and NK cell proliferation and differentiation. Production of chimeras by morula-stage embryo aggregation is an effective way to unravel cell-autonomous hematopoietic defects in gene-targeted mice.
Masuya
Masahiro
M
Department of Veterans Affairs Medical Center, Charleston, SC 29401-5799, USA.
Moussa
Omar
O
Abe
Takanori
T
Deguchi
Takao
T
Higuchi
Tsukasa
T
Ebihara
Yasuhiro
Y
Spyropoulos
Demetri D
DD
Watson
Dennis K
DK
Ogawa
Makio
M
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D002678:Chimera / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology* / Q000378:metabolism*; D005786:Gene Expression Regulation; D018390:Gene Targeting; D006098:Granulocytes / Q000166:cytology* / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; C497426:Fli1 protein, mouse; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators