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

• Published in: Neuron (Cambridge, Mass.) Mass.), 2024-01, Vol.112 (1), p.93-112.e10
• Main Authors: Chen, Jiakun, Stork, Tobias, Kang, Yunsik, Nardone, Katherine A.M., Auer, Franziska, Farrell, Ryan J., Jay, Taylor R., Heo, Dongeun, Sheehan, Amy, Paton, Cameron, Nagel, Katherine I., Schoppik, David, Monk, Kelly R., Freeman, Marc R.
• Format: Article
• Language: English
• Subjects: Animals; astrocyte; Astrocytes - metabolism; Drosophila; Drosophila - metabolism; Drosophila Proteins - metabolism; lipid phosphate phosphatase; morphogenesis; Phospholipids - metabolism; Receptors, G-Protein-Coupled - metabolism; S1pr1; Sphingosine-1-Phosphate Receptors - metabolism; Tre1 GPCR; Zebrafish
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2023.11.008

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 is required for astrocytes to establish their intricate morphology in vivo. The lipid phosphate phosphatases Wunen/Wunen2 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, and live imaging and pharmacology demonstrate that S1pr1 balances proper astrocyte process extension/retraction dynamics during growth. Loss of Tre1 in flies or S1pr1 in zebrafish results in defects in simple assays of motor behavior. Tre1 and S1pr1 are thus potent evolutionarily conserved regulators of the elaboration of astrocyte morphological complexity and, ultimately, astrocyte control of behavior. [Display omitted] •The GPCR Tre1 and LPPs Wun/Wun2 promote astrocyte process outgrowth in Drosophila•Astrocytes compete for growth-promoting phospholipids (PLs) in the CNS•LPPs Wun/Wun2 act locally to regulate PL levels and process outgrowth through Tre1•Vertebrate S1pr1 regulates astrocyte growth through modulation of process dynamics Chen et al. show that the lipid-binding GPCR Tre1/S1pr1 promotes astrocyte morphological growth in Drosophila and zebrafish. Astrocytes compete for local phospholipids, which are processed by the LPPs Wun/Wun2 to promote process outgrowth via Tre1, thereby enabling astrocyte control of behavior.