Astrocyte growth during morphogenesis is driven by the Tre1/S1pr1 phospholipid-binding G protein-coupled receptor

Astrocytes play crucial roles in regulating neural circuit function by forming a dense network of synapse-associated membrane specializations, but signaling pathways regulating astrocyte morphogenesis remain poorly defined. Here we show the Drosophila lipid-binding G protein-coupled receptor (GPCR) Tre1, likely acting through Rac1, is required for astrocytes to elaborate their complex morphology in vivo. The lipid phosphate phosphatases Wunen/Wunen2, which process phospholipid ligands, also regulate astrocyte morphology, and, via Tre1, mediate astrocyte-astrocyte competition for growth promoting lipids. Loss of s1pr1, the functional analog of Tre1 in zebrafish disrupts astrocyte process elaboration. Live-imaging and pharmacology demonstrate that S1pr1 balances proper astrocyte process extension/retraction dynamics during morphogenesis, and that S1pr1 signaling is required throughout astrocyte development. Tre1 and S1pr1 are thus potent evolutionarily conserved regulators of astrocyte growth and elaboration of morphological complexity. The GPCR Tre1 and LPPs Wun/Wun2 promote astrocyte process outgrowth in Drosophila Astrocytes compete for a growthpromoting phospholipid in the CNS Wun/Wun2 act locally to regulate process outgrowth through Tre1 Vertebrate S1pr1 regulates astrocyte growth early, through modulation of process dynamics