We have recently demonstrated that microglia as multipotential stem cells give rise to microtubule-associated protein 2 (MAP2)-positive and glial fibrillary acidic protein (GFAP)-positive cells and that microglia-derived MAP2-positive cells possess properties of functional neurons. In this study, we investigated the molecular pathways involved in the generation of microglia-derived MAP2-positive and GFAP-positive cells. Western blot analyses demonstrated that expression levels of Id2 Protein, an inhibitory basic helix-loop-helix transcription factor of the inhibitor of differentiation and DNA binding family, and Smad proteins were upregulated under differentiation conditions. Immunocytochemical analyses demonstrated that the generation of MAP2-positive and GFAP-positive cells from microglia was promoted by bone morphogenetic proteins (BMPs) and was inhibited by noggin which is a BMP antagonist, Smad4 siRNA and Id2 siRNA, These results indicate that activation of BM P signaling through Smad and Id2 proteins is one of the molecular pathways involved in the generation of microglia-derived MAP2-positive and GFAP-positive cells. (c) 2008 Elsevier Inc. All rights reserved.