Borgen Melissa, Rowland Kimberly, Boerner Jana, Lloyd Brandon, Khan Aruna, Murphey Rodney
Department of Biological Sciences, Florida Atlantic University, Boca Raton, Florida 33431.
Department of Biological Sciences, Florida Atlantic University, Boca Raton, Florida 33431
Genetics. 2017 Mar;205(3):1229-1245. doi: 10.1534/genetics.116.197343. Epub 2017 Jan 18.
The ubiquitin ligase Highwire has a conserved role in synapse formation. Here, we show that Highwire coordinates several facets of central synapse formation in the giant fiber system, including axon termination, axon pruning, and synaptic function. Despite the similarities to the fly neuromuscular junction, the role of Highwire and the underlying signaling pathways are distinct in the fly's giant fiber system. During development, branching of the giant fiber presynaptic terminal occurs and, normally, the transient branches are pruned away. However, in mutants these ectopic branches persist, indicating that Highwire promotes axon pruning. mutants also exhibit defects in synaptic function. Highwire promotes axon pruning and synaptic function cell-autonomously by attenuating a mitogen-activated protein kinase pathway including Wallenda, c-Jun N-terminal kinase/Basket, and the transcription factor Jun. We also show a novel role for Highwire in non-cell autonomous promotion of synaptic function from the midline glia. Highwire also regulates axon termination in the giant fibers, as mutant axons exhibit severe overgrowth beyond the pruning defect. This excessive axon growth is increased by manipulating Fos expression in the cells surrounding the giant fiber terminal, suggesting that Fos regulates a -synaptic signal that promotes giant fiber axon growth.
泛素连接酶Highwire在突触形成中具有保守作用。在此，我们表明Highwire在巨纤维系统中协调中枢突触形成的多个方面，包括轴突终末、轴突修剪和突触功能。尽管与果蝇神经肌肉接头有相似之处，但Highwire的作用及潜在信号通路在果蝇的巨纤维系统中是不同的。在发育过程中，巨纤维突触前终末会发生分支，通常情况下，这些短暂的分支会被修剪掉。然而，在突变体中，这些异位分支会持续存在，这表明Highwire促进轴突修剪。突变体在突触功能方面也表现出缺陷。Highwire通过减弱包括Wallenda、c-Jun氨基末端激酶/Basket和转录因子Jun在内的丝裂原活化蛋白激酶途径，自主地促进轴突修剪和突触功能。我们还展示了Highwire在从中线胶质细胞非自主促进突触功能方面的新作用。Highwire还调节巨纤维中的轴突终末，因为突变体轴突在修剪缺陷之外表现出严重的过度生长。通过操纵巨纤维终末周围细胞中的Fos表达，这种过度的轴突生长会增加，这表明Fos调节一种促进巨纤维轴突生长的突触信号。
