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

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Abstract
Macrophage colony-stimulating factor (M-CSF) induces the proliferation of mononuclear phagocytes, and DAP12 is needed for their function. Colonna and colleagues show that DAP12 is also needed for M-CSF-induced stabilization of β-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 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 β-catenin, which activated genes involved in the cell cycle. DAP12 was essential for phosphorylation and nuclear accumulation of β-catenin. Our results provide a mechanistic explanation for the many defects of DAP12-deficient mononuclear phagocytes.