Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects

• Published in: Blood 2002-01, Vol.99 (1), p.111-120
• Main Authors: Dai, Xu-Ming, Ryan, Gregory R., Hapel, Andrew J., Dominguez, Melissa G., Russell, Robert G., Kapp, Sara, Sylvestre, Vonetta, Stanley, E. Richard
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Count; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Endocytosis; Erythropoiesis; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Gene Targeting; Genotype; Hematopoietic Stem Cells - physiology; Macrophage Colony-Stimulating Factor - deficiency; Macrophage Colony-Stimulating Factor - genetics; Macrophage Colony-Stimulating Factor - physiology; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Molecular and cellular biology; Osteopetrosis - genetics; Phagocytes - physiology; Phenotype; Receptor, Macrophage Colony-Stimulating Factor - deficiency; Receptor, Macrophage Colony-Stimulating Factor - genetics; Receptor, Macrophage Colony-Stimulating Factor - physiology; Reproduction
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V99.1.111

The effects of colony-stimulating factor 1 (CSF-1), the primary regulator of mononuclear phagocyte production, are thought to be mediated by the CSF-1 receptor (CSF-1R), encoded by the c-fms proto-oncogene. To investigate the in vivo specificity of CSF-1 for the CSF-1R, the mouse Csf1r gene was inactivated. The phenotype ofCsf1−/Csf1r− mice closely resembled the phenotype of CSF-1-nullizygous(Csf1op/Csf1op) mice, including the osteopetrotic, hematopoietic, tissue macrophage, and reproductive phenotypes. Compared with their wild-type littermates, splenic erythroid burst-forming unit and high-proliferative potential colony-forming cell levels in bothCsf1op/Csf1op andCsf1−/Csf1r− mice were significantly elevated, consistent with a negative regulatory role of CSF-1 in erythropoiesis and the maintenance of primitive hematopoietic progenitor cells. The circulating CSF-1 concentration inCsf1r−/Csf1r− mice was elevated 20-fold, in agreement with the previously reported clearance of circulating CSF-1 by CSF-1R–mediated endocytosis and intracellular destruction. Despite their overall similarity, several phenotypic characteristics of theCsf1r−/Csf1r− mice were more severe than those of theCsf1op/Csf1op mice. The results indicate that all of the effects of CSF-1 are mediated via the CSF-1R, but that subtle effects of the CSF-1R could result from its CSF-1–independent activation.