Fig. 1 |. Regulation of microglia homeostasis.

a | Microglia are maintained in a cell-autonomous fashion via transforming growth factor-β1 (TGFβ1) signalling, which drives the transcriptional regulation (via the transcription factors PU.1 and/or mothers against decapentaplegic homologue 3 (SMAD3)) of genes that include those encoding the transcription factor MafB (MAFB), Sal-like protein 1 (SALL1), myocyte-specific enhancer factor 2A (MEF2A) and early growth response protein 1 (EGR1)^25,75. Several unique surface receptors — P2Y purinoceptor 12 (P2RY12), transmembrane protein 119 (TMEM119), Fc receptor-like S, scavenger receptor (FCRLS), ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1; also known as CD39) and sialic acid binding Ig-like lectin H, isoform CRA_a (SIGLECH) — identify microglia. P2RY12 senses damaged tissue through the detection of extracellular nucleotides⁵³, whereas ENTPD1 controls microglial process ramification²¹⁸ and its loss is associated with handling-induced seizures in mice²¹⁹. The role of the other receptors is as yet unknown. b | Microglial renewal occurs by local clonal expansion¹³. Furthermore, under certain conditions, lost microglial populations can be replaced with peripherally derived macrophages that are recruited to the CNS. These cells maintain a unique molecular identity and have distinct functional roles as compared with microglia¹⁷, although TMEM119 and other microglial markers may also be expressed by these macrophages²²⁰. Loss of TGFβ1 signalling in these macrophages has been shown to lead to a progressive and fatal demyelinating motor disease¹⁸, suggesting that the manipulation of engrafted myeloid cells has therapeutic potential in neurodegenerative disease. TGFR1 and TGFR2, TGFβ receptors type 1 and 2, respectively.