Schematic diagram illustrating possible mechanisms by which NSCs and microglia interact

Under homoeostasis (A), TLX acts as a transcriptional repressor of a variety of genes in order to maintain NSCs in their proliferative and non-differentiative states by inhibiting gliogenesis (bmp4 pathway), cell-cycle arrest (p21 pathway) and decreased proliferation (pten pathway). Microglia send neurotrophic signals such as BDNF and IGF-1 to NSCs, and receive output from NSCs through CX3CL1/CX3CR1- and CD200/CD200R-mediated pathways. In the TLX knockout mouse (B), microglia become activated (retracted processes coupled with increased levels of endogenous IL-1β) and NSC proliferation and neurogenesis decreases. In the CX3CR1 knockout mouse (C), microglia activation and increased levels of endogenous IL-1β are coupled with reduced TLX expression, up-regulated levels of bmp4 and pten and a reduction in neurogenesis. GFAP: Glial fibrillary acidic protein; Id: Inhibitor of DNA-binding/differentiation protein; BMPR1: Bone morphogenic protein receptor, type 1; bmp4, Bone morphogenic protein 4; BMPR2: Bone morphogenic protein receptor, type 2; SMADS: homologies to the Caenorhabditis elegans SMA (‘small’ worm phenotype) and Drosophila MAD (‘Mothers Against Decapentaplegic’) family of genes; P: phosphorylation; SMAD4: Mothers against decapentaplegic homologue 4; CoREST: REST (RE1-silencing transcription factor) corepressor 1; TLX: Protein Tailless Homologue; Nr2e1: Nuclear receptor subfamily 2 Group E Member 1; Me: methylation.