Microglia could show both protective and deleterious influences on neurons after nerve injury. In the control of microglial phenotypes, molecules expressed on microglial surfaces are assumed to play crucial roles. DNAX activation protein of 12 kDa (Dap12), which is a transmembrane adaptor protein known to regulate activation of osteoclasts and macrophages, is also expressed by microglia in the nervous system. Although implications of microglial DAP12 signaling in pathogenesis of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and sporadic amyotrophic lateral sclerosis have been demonstrated, little is known about DAP12 functions in fate of injured motor neurons. Here we show that DAP12 expression was specifically induced in microglia in nerve-injured hypoglossal nuclei. Nerve injury-activated microglia in DAP12 knockout (KO) mice returned to a normal condition earlier and exhibited suppressed expression of pro-inflammatory cytokines compared with the wild type mice. In line with the changes of microglial gene expressions in vivo, mRNA expressions for inflammatory cytokines were also suppressed in lipopolysaccharide-activated primary microglia prepared from DAP12 KO mice in vitro. In consequence of these microglial characteristics, we observed in vivo that survival ratio of neuron after hypoglossal nerve injury significantly increased in the DAP12 KO mice. These results suggest that DAP12 mediated signals may prolong activation of microglia and enhance neurotoxicity after motor nerve injury.