DFsn collaborates with Highwire to down-regulate the Wallenda/DLK kinase and restrain synaptic terminal growth

We identified DFsn as an F-box protein that binds to the RING-domain ubiquitin ligase Highwire and that can localize to the Drosophila neuromuscular junction. Loss-of-function mutants for DFsn have a phenotype that is very similar to highwire mutants – there is a dramatic overgrowth of synaptic termini, with a large increase in the number of synaptic boutons and branches. In addition, synaptic transmission is impaired in DFsn mutants. Genetic interactions between DFsn and highwire mutants indicate that DFsn and Highwire collaborate to restrain synaptic terminal growth. Finally, DFsn regulates the levels of the Wallenda/DLK kinase, and wallenda is necessary for DFsn-dependent synaptic terminal overgrowth.The F-box protein DFsn binds the ubiquitin ligase Highwire and is required to down-regulate the levels of the Wallenda/DLK kinase and restrain synaptic terminal growth. We propose that DFsn and Highwire participate in an evolutionarily conserved ubiquitin ligase complex whose substrates regulate the structure and function of synapses.The connectivity and functionality of a neural circuit depends on the structure of its constituent neurons' presynaptic fields. Different neurons make very different synaptic trees – a serotonergic neuron will synapse with thousands of neurons throughout the brain, while climbing fibers from the medulla may synapse with only a single Purkinje cell in the cerebellum. Individual neurons with the same identity can also have different sized synaptic arbors and this has functional consequences: during synaptic competition at the vertebrate neuromuscular junction (NMJ), motoneurons with larger arbors are at a disadvantage when competing against those with smaller arbors [1]. Molecular mechanisms that control the size and structure of a neuron's presynaptic field are key regulators of the development, function, and plasticity of neural circuits.In Drosophila, genetic studies have identified a number of signaling pathways that regulate the morph