Abstract
Lipids are structural components of cellular membranes and signaling molecules that are widely involved in development and diseases, but the underlying molecular mechanisms are poorly understood, partly because of the vast variety of lipid species and complexity of synthetic and turnover pathways. From a genetic screen, we identify that mannosyl glucosylceramide (MacCer), a species of glycosphingolipid (GSL), promotes synaptic bouton formation at the Drosophila neuromuscular junction (NMJ). Pharmacological and genetic analysis shows that the NMJ growth-promoting effect of MacCer depends on normal lipid rafts, which are known to be composed of sphingolipids, sterols and select proteins. MacCer positively regulates the synaptic level of Wnt1/Wingless (Wg) and facilitates presynaptic Wg signaling, whose activity is raft-dependent. Furthermore, a functional GSL-binding motif in Wg exhibiting a high affinity for MacCer is required for normal NMJ growth. These findings reveal a novel mechanism whereby the GSL MacCer promotes synaptic bouton formation via Wg signaling.
Highlights
The glycosphingolipids (GSLs) are abundant in the nervous system and are essential for brain development (Fantini and Yahi, 2015; Yu et al, 2009)
We found that mutations in sphingosine kinase 2 (Sk2) resulted in more satellite boutons at neuromuscular junction (NMJ) (Figure 1G,J), in contrast to the fewer and larger bouton phenotype in lace and schlank mutants
These results indicate that the de novo synthesis of ceramides, their downstream derivatives, or both promote bouton formation and NMJ growth
Summary
The glycosphingolipids (GSLs) are abundant in the nervous system and are essential for brain development (Fantini and Yahi, 2015; Yu et al, 2009). Expression of egh in muscles (postsynaptic) driven by C57-Gal4 or in glia driven by Repo-Gal4 did not affect NMJ growth in both wild type and egh62d18 mutant background (Figure 2—figure supplement 2).
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