HighwireFunction at theDrosophilaNeuromuscular Junction: Spatial, Structural, and Temporal Requirements

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Abstract
Highwire is a huge, evolutionarily conserved protein that is required to restrain synaptic growth and promote synaptic transmission at theDrosophilaneuromuscular junction. Current models ofhighwirefunction suggest that it may act as a ubiquitin ligase to regulate synaptic development. However, it is not known in which cellshighwirefunctions, whether its putative ligase domain is required for function, or whetherhighwireregulates the synapse during development or alternatively sets cell fate in the embryo. We performed a series of transgenic rescue experiments to test the spatial, structural, and temporal requirements forhighwirefunction. We find that presynaptic activity ofhighwireis both necessary and sufficient to regulate both synapse morphology and physiology. The Highwire RING domain, which is postulated to function as an E3 ubiquitin ligase, is required forhighwirefunction. In addition,highwireacts throughout larval development to regulate synaptic morphology and function. Finally, we show that the morphological and physiological phenotypes ofhighwiremutants have different dosage and temporal requirements forhighwire, demonstrating thathighwiremay independently regulate the molecular pathways controlling synaptic growth and function.