Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and beta-catenin

Nat Immunol. 2009 Jul;10(7):734-43. doi: 10.1038/ni.1744. Epub 2009 Jun 7.


Macrophage colony-stimulating factor (M-CSF) influences the proliferation and survival of mononuclear phagocytes through the receptor CSF-1R. The adaptor protein DAP12 is critical for the function of mononuclear phagocytes. DAP12-mutant mice and humans have defects in osteoclasts and microglia, as well as brain and bone abnormalities. Here we show DAP12 deficiency impaired the M-CSF-induced proliferation and survival of macrophages in vitro. DAP12-deficient mice had fewer microglia in defined central nervous system areas, and DAP12-deficient progenitors regenerated myeloid cells inefficiently after bone marrow transplantation. Signaling by M-CSF through CSF-1R induced the stabilization and nuclear translocation of beta-catenin, which activated genes involved in the cell cycle. DAP12 was essential for phosphorylation and nuclear accumulation of beta-catenin. Our results provide a mechanistic explanation for the many defects of DAP12-deficient mononuclear phagocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Calcium-Binding Proteins / metabolism
  • Cell Adhesion / drug effects
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Flow Cytometry
  • Focal Adhesion Kinase 2 / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Immunoblotting
  • Immunohistochemistry
  • Macrophage Colony-Stimulating Factor / pharmacology*
  • Macrophages / cytology
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Knockout
  • Mice, Transgenic
  • Microfilament Proteins
  • Phosphorylation
  • Signal Transduction / drug effects*
  • beta Catenin / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Aif1 protein, mouse
  • Calcium-Binding Proteins
  • Microfilament Proteins
  • Tyrobp protein, mouse
  • beta Catenin
  • Green Fluorescent Proteins
  • Macrophage Colony-Stimulating Factor
  • Focal Adhesion Kinase 2
  • Ptk2b protein, mouse