Nervous system development and function are tightly regulated by metabolic processes, including the metabolism of lipids such as fatty acids (FAs). Mutations in long-chain acyl-CoA synthetase 4 (ACSL4) are associated with non-syndromic intellectual disabilities. We previously reported that Acsl, the Drosophila ortholog of mammalian ACSL3 and ACSL4, inhibits neuromuscular synapse growth by suppressing transforming growth factor-β/bone morphogenetic protein (BMP) signaling. Here, we report that Acsl regulates the composition of FAs and membrane lipid, which in turn affect neuromuscular junction (NMJ) synapse development. Acsl mutant brains had decreased abundance of C16:1 fatty acyls; restoration of Acsl expression abrogated NMJ overgrowth and the increase in BMP signaling. A lipidomic analysis revealed that Acsl suppressed the levels of three lipid raft components in the brain, including mannosyl glucosylceramide (MacCer), phosphoethanolamine ceramide, and ergosterol. MacCer level was elevated in Acsl mutant NMJs and along with sterol promoted NMJ overgrowth but was not associated with the increase in BMP signaling in the mutants. These findings suggest that Acsl inhibits NMJ growth by stimulating C16:1 and concomitantly suppressing raft-associated lipid levels.
- Received July 15, 2016.
- Accepted September 16, 2016.
- © 2016. Published by The Company of Biologists Ltd