The Tre1/S1pr1 phospholipid-binding G protein-coupled receptor signaling pathway is required for astrocyte morphogenesis

Astrocytes play crucial roles in regulating neural circuit function by forming a dense network of synapse-associated membrane specializations. Intimate astrocyte-synapse contact is thought to be crucial for astrocyte function, yet 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 morphologies. The lipid phosphate phosphatases Wunen/Wunen2, which process phospholipid ligands for Tre1, also regulate astrocyte growth, and act upstream of Tre1 as Wunen/Wunen2-mediated astrocyte overgrowth is suppressed by Tre1 loss. Loss of s1pr1, the functional analog of Tre1 in zebrafish, also leads to disruption of astrocyte morphogenesis. 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. Our work identifies lipid-binding GPCRs like Tre1 and S1pr1 as potent evolutionarily conserved regulators of astrocyte morphological complexity. ### Competing Interest Statement The authors have declared no competing interest.