Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization.
Mice lacking granulocyte colony-stimulating factor (G-CSF) were generated by targeted disruption of the G-CSF gene in embryonal stem cells. G-CSF-deficient mice (genotype G-CSF-/-) are viable, fertile, and superficially healthy, but have a chronic neutropenia. Peripheral blood neutrophil levels were 20% to 30% of wild-type mice (genotype G-CSF+/+) and mice heterozygous for the null mutation had intermediate neutrophil levels, suggesting a gene-dosage effect. In the marrow of G-CSF-/- mice, granulopoietic precursor cells were reduced by 50% and there were reduced levels of granulocyte, macrophage, and blast progenitor cells. Despite G-CSF deficiency, mature neutrophils were still present in the blood and marrow, indicating that other factors can support neutrophil production in vivo. G-CSF-/- mice had reduced numbers of neutrophils available for rapid mobilization into the circulation by a single dose of G-CSF. G-CSF administration reversed the granulopoietic defect of G-CSF-/- mice. One day of G-CSF administration to G-CSF-/- mice elevated circulating neutrophil levels to normal, and after 4 days of G-CSF administration, G-CSF+/+ and G-CSF-/- marrows were morphologically indistinguishable. G-CSF-/- mice had a markedly impaired ability to control infection with Listeria monocytogenes, with diminished neutrophil and delayed monocyte increases in the blood and reduced infection-driven granulopoiesis. Collectively, these observations indicate that G-CSF is indispensible for maintaining the normal quantitative balance of neutrophil production during "steady-state" granulopoiesis in vivo and also implicate G-CSF in "emergency" granulopoiesis during infections.
Lieschke
G J
GJ
Melbourne Tumor Biology Branch, Ludwig Institute for Cancer Research, Parkville, Victoria, Australia.
Grail
D
D
Hodgson
G
G
Metcalf
D
D
Stanley
E
E
Cheers
C
C
Fowler
K J
KJ
Basu
S
S
Zhan
Y F
YF
Dunn
A R
AR
D000818:Animals; D001483:Base Sequence; D005838:Genotype; D016179:Granulocyte Colony-Stimulating Factor / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D006098:Granulocytes / Q000473:pathology*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000469:parasitology*; D007958:Leukocyte Count; D008088:Listeriosis / Q000473:pathology; D008264:Macrophages / Q000473:pathology*; D051379:Mice; D008969:Molecular Sequence Data; D009503:Neutropenia / Q000209:etiology*; D009504:Neutrophils / Q000502:physiology*
D016179:Granulocyte Colony-Stimulating Factor