Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Beijing, China.
Sino-Danish College, Sino-Danish Center for Education and Research, Chinese Academy of Sciences, Beijing, China.
Elife. 2018 Oct 25;7:e38183. doi: 10.7554/eLife.38183.
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 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.
脂质是细胞膜的结构成分和信号分子，广泛参与发育和疾病，但潜在的分子机制还不清楚，部分原因是脂质种类繁多，合成和周转途径复杂。通过遗传筛选，我们发现甘露糖葡糖神经酰胺（MacCer），一种糖鞘脂（GSL），可促进神经肌肉接头（NMJ）处的突触小泡形成。药理和遗传分析表明，MacCer 促进 NMJ 生长的作用依赖于正常的脂筏，已知脂筏由鞘脂、固醇和选择蛋白组成。MacCer 正向调节 Wnt1/Wingless（Wg）的突触水平，并促进依赖于筏的突触前 Wg 信号转导。此外，Wg 中具有与 MacCer 高亲和力的功能糖脂结合基序是 NMJ 正常生长所必需的。这些发现揭示了一种新的机制，即 GSL MacCer 通过 Wg 信号促进突触小泡形成。
