Kimmel Center for Biology and Medicine of the Skirball Institute and Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA.
J Neurosci. 2010 Nov 17;30(46):15358-68. doi: 10.1523/JNEUROSCI.1862-10.2010.
Liprin-α proteins are adaptors that interact with the receptor protein tyrosine phosphatase leukocyte common antigen-related (LAR) and other synaptic proteins to promote synaptic partner selection and active zone assembly. Liprin-β proteins bind to and share homology with Liprin-α proteins, but their functions at the synapse are unknown. The Drosophila genome encodes single Liprin-α and Liprin-β homologs, as well as a third related protein that we named Liprin-γ. We show that both Liprin-β and Liprin-γ physically interact with Liprin-α and that Liprin-γ also binds to LAR. Liprin-α mutations have been shown to disrupt synaptic target layer selection by R7 photoreceptors and to reduce the size of larval neuromuscular synapses. We have generated null mutations in Liprin-β and Liprin-γ to investigate their role in these processes. We find that, although Liprin-α mutant R7 axons terminate before reaching the correct target layer, Liprin-β mutant R7 axons grow beyond their target layer. Larval neuromuscular junction size is reduced in both Liprin-α and Liprin-β mutants, and further reduced in double mutants, suggesting independent functions for these Liprins. Genetic interactions demonstrate that both Liprin proteins act through the exchange factor Trio to promote stable target selection by R7 photoreceptor axons and growth of neuromuscular synapses. Photoreceptor and neuromuscular synapses develop normally in Liprin-γ mutants; however, removing Liprin-γ improves R7 targeting in Liprin-α mutants, and restores normal neuromuscular junction size to Liprin-β mutants, suggesting that Liprin-γ counteracts the functions of the other two Liprins. We propose that context-dependent interactions between the three Liprins modulate their functions in synapse formation.
脂质连接蛋白-α 蛋白是一种衔接蛋白，它与受体蛋白酪氨酸磷酸酶白细胞共同抗原相关（LAR）和其他突触蛋白相互作用，促进突触伴侣的选择和活性区的组装。脂质连接蛋白-β 蛋白与脂质连接蛋白-α 蛋白结合，并具有同源性，但它们在突触中的功能尚不清楚。果蝇基因组编码单个脂质连接蛋白-α和脂质连接蛋白-β同源物，以及我们命名为脂质连接蛋白-γ的第三种相关蛋白。我们表明，脂质连接蛋白-β和脂质连接蛋白-γ都与脂质连接蛋白-α相互作用，并且脂质连接蛋白-γ也与 LAR 结合。脂质连接蛋白-α 的突变已被证明会破坏 R7 光感受器的突触靶层选择，并减小幼虫肌肉突触的大小。我们已经产生了脂质连接蛋白-β 和脂质连接蛋白-γ 的缺失突变，以研究它们在这些过程中的作用。我们发现，尽管脂质连接蛋白-α 突变体 R7 轴突在到达正确的靶层之前就已经终止，但脂质连接蛋白-β 突变体 R7 轴突却延伸超出了它们的靶层。幼虫肌肉突触的大小在脂质连接蛋白-α 和脂质连接蛋白-β 突变体中均减小，并且在双突变体中进一步减小，这表明这两种脂质连接蛋白具有独立的功能。遗传相互作用表明，这两种脂质连接蛋白都通过交换因子 Trio 发挥作用，以促进 R7 光感受器轴突的稳定靶标选择和肌肉突触的生长。脂质连接蛋白-γ 突变体中的光感受器和肌肉突触发育正常；然而，去除脂质连接蛋白-γ 可以改善脂质连接蛋白-α 突变体中的 R7 靶向，并且将脂质连接蛋白-β 突变体中的正常肌肉突触大小恢复正常，这表明脂质连接蛋白-γ 拮抗了其他两种脂质连接蛋白的功能。我们提出，这三种脂质连接蛋白之间的上下文相关相互作用调节它们在突触形成中的功能。
