Glia phagocytose neuronal sphingolipids to infiltrate developing synapses

The complex morphologies of mature neurons and glia emerge through profound rearrangements of cell membranes during development. Despite being integral components of these membranes, it is unclear whether lipids might actively sculpt these morphogenic processes. By analyzing lipid levels in the developing fruit fly brain, we discover dramatic increases in specific sphingolipids coinciding with neural circuit establishment. Disrupting this sphingolipid bolus via genetic perturbations of sphingolipid biosynthesis and catabolism leads to impaired glial autophagy. Remarkably, glia can obtain sphingolipid precursors needed for autophagy by phagocytosing neurons. These precursors are then converted into specific long-chain ceramide phosphoethanolamines (CPEs), invertebrate analogs of sphingomyelin. These lipids are essential for glia to arborize and infiltrate the brain, a critical step in circuit maturation that when disrupted leads to reduced synapse numbers. Taken together, our results demonstrate how spatiotemporal tuning of sphingolipid metabolism during development plays an instructive role in programming brain architecture. HighlightsO_LIBrain sphingolipids (SLs) remodel to very long-chain species during circuit maturation C_LIO_LIGlial autophagy requires de novo SL biosynthesis coordinated across neurons and glia C_LIO_LIGlia evade a biosynthetic blockade by phagolysosomal salvage of neuronal SLs C_LIO_LICeramide Phosphoethanolamine is critical for glial infiltration and synapse density C_LI