Two Distinct E3 Ubiquitin Ligases Have Complementary Functions in the Regulation of Delta and Serrate Signaling in <italic>Drosophila</italic>

Signaling by the Notch ligands Delta (Dl) and Serrate (Ser) regulates a wide variety of essential cell-fate decisions during animal development. Two distinct E3 ubiquitin ligases, Neuralized (Neur) and Mind bomb (Mib), have been shown to regulate Dl signaling in <named-content content-type="genus-species">Drosophila melanogaster</named-content> and <italic>Danio rerio,</italic> respectively. While the <italic>neur</italic> and <italic>mib</italic> genes are evolutionarily conserved, their respective roles in the context of a single organism have not yet been examined. We show here that the <italic>Drosophila mind bomb (D-mib)</italic> gene regulates a subset of Notch signaling events, including wing margin specification, leg segmentation, and vein determination, that are distinct from those events requiring <italic>neur</italic> activity. <italic>D-mib</italic> also modulates lateral inhibition, a <italic>neur</italic>- and <italic>Dl</italic>-dependent signaling event, suggesting that D-mib regulates Dl signaling. During wing development, expression of <italic>D-mib</italic> in dorsal cells appears to be necessary and sufficient for wing margin specification, indicating that D-mib also regulates Ser signaling. Moreover, the activity of the <italic>D-mib</italic> gene is required for the endocytosis of Ser in wing imaginal disc cells. Finally, ectopic expression of <italic>neur</italic> in <italic>D-mib</italic> mutant larvae rescues the wing <italic>D-mib</italic> phenotype, indicating that Neur can compensate for the lack of <italic>D-mib</italic> activity. We conclude that D-mib and Neur are two structurally distinct proteins that have similar molecular activities but distinct developmental functions in <italic>Drosophila</italic>.