Glia phagocytose neuronal sphingolipids to infiltrate developing synapses

Emma K Theisen; Irma Magaly Rivas-Serna; Ryan J Lee; Taylor R Jay; Govind Kunduri; Tasha T Nguyen; Vera Mazurak; M Thomas Clandinin; Thomas R Clandinin; John P Vaughen

doi:10.1101/2025.04.14.648777

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Glia phagocytose neuronal sphingolipids to infiltrate developing synapses

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Glia phagocytose neuronal sphingolipids to infiltrate developing synapses

Emma K Theisen, Irma Magaly Rivas-Serna, Ryan J Lee, Taylor R Jay, Govind Kunduri, Tasha T Nguyen, Vera Mazurak, M Thomas Clandinin, Thomas R Clandinin and John P Vaughen

bioRxiv

Cold Spring Harbor Laboratory

04/22/2025

DOI: 10.1101/2025.04.14.648777

PMCID: PMC12045345

PMID: 40313927

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https://doi.org/10.1101/2025.04.14.648777View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

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.

Biosynthesis

phagocytosis

autophagy

sphingolipids

endolysosome

GBA

catabolism

glia

arborization

SPT

VLCFA

ceramide phosphoethanolamine

sphingomyelin

Details

Title: Subtitle: Glia phagocytose neuronal sphingolipids to infiltrate developing synapses
Creators: Emma K Theisen - Stanford University
Irma Magaly Rivas-Serna
Ryan J Lee - Stanford University
Taylor R Jay - Oregon Health & Science University
Govind Kunduri - National Cancer Institute
Tasha T Nguyen - Stanford University
Vera Mazurak
M Thomas Clandinin
Thomas R Clandinin - Stanford University
John P Vaughen - University of California, San Francisco
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.1101/2025.04.14.648777
PMID: 40313927
PMCID: PMC12045345
NLM abbreviation: bioRxiv
ISSN: 2692-8205
eISSN: 2692-8205
Publisher: Cold Spring Harbor Laboratory; United States
Number of pages: 63 pages
Grant note: P30 EY026877 / NEI NIH HHS P40 OD018537 / NIH HHS R24 OD030002 / NIH HHS K99 NS133298 / NINDS NIH HHS
Language: English
Date posted: 04/22/2025
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9985113263202771

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