Sheehan, A. | bioRxiv Science

bioRxiv2022

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, 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. O_LIThe GPCR Tre1 and LPPs Wun/Wun2 promote astrocyte process outgrowth in Drosophila C_LIO_LIAstrocytes compete for a growth{-}promoting phospholipid in the CNS C_LIO_LIWun/Wun2 act locally to regulate process outgrowth through Tre1 C_LIO_LIVertebrate S1pr1 regulates astrocyte growth early, through modulation of process dynamics C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/508188v2_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1e86db5org.highwire.dtl.DTLVardef@7abd6borg.highwire.dtl.DTLVardef@29f163org.highwire.dtl.DTLVardef@1a6c4b9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Glial TGFβ activity promotes axon survival in peripheral nerves

Axons can represent the majority of the volume of a neuron and are energetically very demanding. Specialized glia ensheathe axons and are believed to support axon function and maintenance throughout life, but molecular details of glia-neuron support mechanisms remain poorly defined. Here we identify a collection of secreted and transmembrane genes that are required in glia for long-term axon survival in vivo. We show that key components of the TGF{beta} superfamily are required cell-autonomously in glia for peripheral nerve maintenance, although their loss does not disrupt glial morphology. We observe age-dependent neurodegeneration in the absence of glial TGF{beta} signaling that can be rescued by genetic blockade of Wallerian degeneration. Our data argue that glial TGF{beta} signaling normally acts to promote axon survival and suppress neurodegeneration. Significance StatementAxon maintenance is critical to preserving the functional integrity of the nervous system across animal lifespan. Glia contribute to axon maintenance, but their precise roles remain to be fully characterized. We identify glial genes that regulate axon support and provide new molecular insight into the means by which glia promote axon survival, which may help explain why neurodegeneration occurs when glia are lost in disease. We show that TGF{beta} signaling in mature glia is essential for long-term maintenance of axons, and that loss of TGF{beta} signaling activates an axon death signaling pathway.

neuroscience↗