School of Life Science and Technology, The Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, 210096, China.
School of Biological Sciences, Monash University, Clayton, VIC, 3800, Australia.
Commun Biol. 2023 Oct 18;6(1):1056. doi: 10.1038/s42003-023-05428-3.
Neuroligins are transmembrane cell adhesion proteins well-known for their genetic links to autism spectrum disorders. Neuroligins can function by regulating the actin cytoskeleton, however the factors and mechanisms involved are still largely unknown. Here, using the Drosophila neuromuscular junction as a model, we reveal that F-Actin assembly at the Drosophila NMJ is controlled through Cofilin signaling mediated by an interaction between DNlg2 and RACK1, factors not previously known to work together. The deletion of DNlg2 displays disrupted RACK1-Cofilin signaling pathway with diminished actin cytoskeleton proteo-stasis at the terminal of the NMJ, aberrant NMJ structure, reduced synaptic transmission, and abnormal locomotion at the third-instar larval stage. Overexpression of wildtype and activated Cofilin in muscles are sufficient to rescue the morphological and physiological defects in dnlg2 mutants, while inactivated Cofilin is not. Since the DNlg2 paralog DNlg1 is known to regulate F-actin assembly mainly via a specific interaction with WAVE complex, our present work suggests that the orchestration of F-actin by Neuroligins is a diverse and complex process critical for neural connectivity.
神经连接蛋白是一种细胞表面黏附蛋白，其与自闭症谱系障碍的遗传联系广为人知。神经连接蛋白可以通过调节肌动蛋白细胞骨架来发挥作用，但涉及的因素和机制在很大程度上仍不清楚。在这里，我们使用果蝇的神经肌肉接头作为模型，揭示了果蝇 NMJ 中的 F-肌动蛋白组装是通过 DNlg2 和 RACK1 之间的相互作用介导的 Cofilin 信号通路来控制的，这两个因素以前没有被认为是一起工作的。DNlg2 的缺失显示出 RACK1-Cofilin 信号通路的破坏，NMJ 末端的肌动蛋白细胞骨架稳定性降低，NMJ 结构异常，突触传递减少，以及三龄幼虫阶段的异常运动。在肌肉中过表达野生型和激活型 Cofilin 足以挽救 dnlg2 突变体的形态和生理缺陷，而失活型 Cofilin 则不能。由于已知 DNlg2 同源物 DNlg1 主要通过与 WAVE 复合物的特定相互作用来调节 F-肌动蛋白组装，我们目前的工作表明，神经连接蛋白对 F-肌动蛋白的调控是一个多样化和复杂的过程，对神经连接至关重要。
