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

Abstract

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.

Developmental and age-related synapse elimination is mediated by glial Croquemort

“…We next evaluated whether fly glia use similar molecular pathways to regulate synapse numbers in comparison to astrocytes in mammals. We first analyzed a TRAPseq dataset we generated 27 to assess changes in astrocyte gene translation across the developmental time points we identified as important periods of synapse formation and elimination (Fig S1B,Fig 1K). We found that orthologs to genes associated with synapse formation, tsp (TSP1/2) 11 and sparc (Sparc / Hevin) 12 , and synapse elimination, drpr (Megf10) 13 , were expressed in astrocytes during the developmental times when these processes occur in the fly (Fig 1L).…”

“…This dataset is publically available through GEO (accession #GSE242729) and the methods for obtaining these results have been detailed previously 27 . Briefly, an eGFP-tagged L10a ribosomal subunit was expressed in astrocytes using alrm-Gal4, elaV-Gal80.…”