Unidirectional Notch signaling depends on continuous cleavage of Delta

Unidirectional signaling from cells expressing Delta (DI) to cells expressing Notch is a key feature of many developmental processes. We demonstrate that the Drosophila ADAM metalloprotease Kuzbanian-like (Kul) plays a key role in promoting this asymmetry. Kul cleaves DI efficiently both in cell culture and in flies, and has previously been shown not to be necessary for Notch processing during signaling. In the absence of Kul in the developing wing, the level of DI in cells that normally receive the signal is elevated, and subsequent alterations in the directionality of Notch signaling lead to prominent phenotypic defects. Proteolytic cleavage of DI by Kul represents a general mechanism for refining and maintaining the asymmetric distribution of DI. in cases where transcriptional repression of DI expression does not suffice to eliminate DI protein.