Fig. 1

TREM2 and PLCγ2 functions, and signalling networks regulating their activation in microglia. a Summary of the microglial physiological functions associated with TREM2 and PLCγ2 activation. b A representation of some candidate proteins that are expressed in microglia and maintain TREM2/DAP12 in an inactive state. In absence of activating signals, PLCγ2 is neither recruited to the membrane or activated but instead maintained in its autoinhibited form in the cytoplasm. c A possible, simplified, model for the signalling from ligand bound TREM2, through DAP12 and non-receptor kinases (such as Syk and Src) to the adapter protein LAT2/BLNK. Tyrosine phosphorylation on membrane localised adaptors like LAT2 allow the recruitment of signalling proteins like PLCγ2 and other molecules to the vicinity of the plasma membrane where their substrate PIP₂ is localised. d Model for recruitment and activation of PLCγ2 and consequences of PLCγ2 activity in microglial cell signalling, survival and phagocytosis. In addition to interactions with the adaptors that mainly contribute to the recruitment, a number of proteins have been shown to be important for PLCγ2 activation in various immune cells; these include BTK and Syk kinases, mediating tyrosine phosphorylation, and a small-GTPase Rac that could contribute to phosphorylation-independent activation. The relative importance of these inputs in microglia remains to be elucidated