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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  Drosophila melanogaster  and  Danio rerio,  respectively. While the  neur  and  mib  genes are evolutionarily conserved, their respective roles in the context of a single organism have not yet been examined. We show here that the  Drosophila mind bomb (D-mib)  gene regulates a subset of Notch signaling events, including wing margin specification, leg segmentation, and vein determination, that are distinct from those events requiring  neur  activity.  D-mib  also modulates lateral inhibition, a  neur - and  Dl -dependent signaling event, suggesting that D-mib regulates Dl signaling. During wing development, expression of  D-mib  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  D-mib  gene is required for the endocytosis of Ser in wing imaginal disc cells. Finally, ectopic expression of  neur  in  D-mib  mutant larvae rescues the wing  D-mib  phenotype, indicating that Neur can compensate for the lack of  D-mib  activity. We conclude that D-mib and Neur are two structurally distinct proteins that have similar molecular activities but distinct developmental functions in  Drosophila .

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