Credit: Haibei Zhang

In all organisms with a nervous system, the construction of functional neural circuits requires a precise choreography of developmental events that includes the growth and guidance of axons to their proper targets and the formation of mature synapses. Studies in species ranging from worms to mice have revealed that proteins from the PHR (Pam/Highwire/RPM-1) family of E3 ubiquitin ligases modulate neural development via the formation of an F-box protein–containing complex and activation of the MAP kinase signaling cascade. Despite these advances in our understanding of the components and activities of these integral protein complexes, it is still unclear as to how the essential PHR proteins themselves are regulated during development. On page 1267, Tian and colleagues identify Rae1 as a binding partner of the Drosophila PHR protein Highwire (Hiw) that acts to prevent its degradation and promote refinement of the presynaptic terminal.

The authors identified Rae1 as a Hiw complex–associating protein using tandem affinity purification and liquid chromatography–tandem mass spectrometry. Flies expressing only a mutant form of Rae1 exhibited a concurrent increase in neuromuscular junction synaptic bouton number and a decrease in bouton size, a phenotype that mimics that observed in hiw null mutants. Notably, mutation of Rae1 also resulted in a decrease in the neuronal levels of Hiw protein (but not mRNA), suggesting that Rae1 acts to prevent post-translational degradation of Hiw. Indeed, blocking autophagy was sufficient to rescue both Hiw protein levels and synaptic bouton overgrowth even in the presence of mutated Rae1, whereas overexpression of wild-type Rae1 blocked Hiw degradation in the presence of the autophagy-promoting protein Atg1. Taken together, these results suggest that Rae1 is an integral member of the PHR E3 ubiquitin ligase complex that acts to promote synaptic refinement by maintaining Hiw protein levels during development.