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

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 unction of mononuclear phagocytes. DAP12-mutant mice and humans have defects in osteoclasts and microglia, as well as rain and bone abnormalities. Here we show DAP12 deficiency impaired the M-CSF-induced proliferation and survival of acrophages in vitro. DAP12-deficient mice had fewer microglia in defined central nervous system areas, and DAP12-deficient rogenitors regenerated myeloid cells inefficiently after bone arrow transplantation. Signaling by M-CSF through CSF-1R induced the stabilization and nuclear translocation of b-catenin, which activated genes involved in the cell cycle. DAP12 was essential for phosphorylation and nuclear accumulation of b-catenin. Our results provide a mechanistic explanation for the many defects of DAP12-deficient mononuclear phagocytes.