An intercellular metabolic relay for brain sparingin Drosophila

Franchet, A.; Jin, Y.; Newell, C. L.; Girard, V.; Maniere, G.; Grosjean, Y.; Barrington, C.; MacRae, J. I.; Gilmore, I. S.; Gould, A. P.

doi:10.1101/2025.04.02.645514

bioRxiv · 10.1101/2025.04.02.645514

An intercellular metabolic relay for brain sparingin Drosophila

Franchet, A.·Jin, Y.·Newell, C. L.·Girard, V.·Maniere, G.·Grosjean, Y.·Barrington, C.·MacRae, J. I.·Gilmore, I. S.·Gould, A. P.

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Abstract

Brain sparing protects growth of the central nervous system (CNS) at the expense of other developing organs during nutrient restriction. This survival strategy is conserved from Drosophila to mammals but little is known about its underlying metabolic mechanisms. Here, we show that CNS uptake and catabolism of circulating glutamine is essential for neural stem cell proliferation during brain sparing but not normal brain development. Glutamine is imported into perineurial glia of the blood-brain-barrier, which upregulate glutaminase (Gls) and vesicular glutamate transporter 1 (VGlut1) to promote glutaminolysis and glutamate secretion. Neural stem cells then import released glutamate via excitatory amino acid transporter 1 (Eaat1) and maintain it at homeostatic levels via glutamine synthetase 1 (Gs1). Glutamine nitrogen contributes surprisingly little to newly synthesized DNA or protein in neural stem cells but its carbon fuels the oxidative tricarboxylic acid cycle. These findings identify an intercellular metabolic relay specifically required to sustain the proliferation of neural stem cells during brain sparing.

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Franchet, A., Jin, Y., Newell, C. L., Girard, V., Maniere, G., Grosjean, Y., Barrington, C., MacRae, J. I., Gilmore, I. S., Gould, A. P.. 2025-04-03. An intercellular metabolic relay for brain sparingin Drosophila. https://doi.org/10.1101/2025.04.02.645514

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