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

Blood. 2002 Jan 1;99(1):111-20. doi: 10.1182/blood.v99.1.111.

Abstract

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 of Csf1(-)/Csf1r(-) mice closely resembled the phenotype of CSF-1-nullizygous (Csf1(op)/Csf1(op)) 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 both Csf1(op)/Csf1(op) and Csf1(-)/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 in Csf1r(-)/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 the Csf1r(-)/Csf1r(-) mice were more severe than those of the Csf1(op)/Csf1(op) 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Count
  • Endocytosis
  • Erythropoiesis
  • Flow Cytometry
  • 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
  • Osteopetrosis / genetics*
  • Phagocytes / physiology*
  • Phenotype
  • Receptor, Macrophage Colony-Stimulating Factor / deficiency
  • Receptor, Macrophage Colony-Stimulating Factor / genetics*
  • Receptor, Macrophage Colony-Stimulating Factor / physiology*
  • Reproduction*

Substances

  • Macrophage Colony-Stimulating Factor
  • Receptor, Macrophage Colony-Stimulating Factor