Presenilin-mediated transmembrane cleavage is required for Notch signal transduction in Drosophila

The cleavage model for signal transduction by receptors of the LIN-12/Notch family posits that ligand binding leads to cleavage within the transmembra ne domain, so that the intracellular domain is released to translocate to t he nucleus and activate target gene expression. The familial Alzheimer's di sease-associated protein Presenilin is required for LIN-12/Notch signaling, and several lines of evidence suggest that Presenilin mediates the transme mbrane cleavage event that releases the LIN-12/Notch intracellular domain. However, doubt was cast on this possibility by a report that Presenilin is not required for the transducing activity of N-ECN, a constitutively active transmembrane form of Notch, in Drosophila, Here, we have reassessed this finding and show instead that Presenilin is required for activity of N-ECN for all cell fate decisions examined. Our results indicate that transmembra ne cleavage and signal transduction are strictly correlated, supporting the cleavage model for signal transduction by LIN-12/Notch and a role for Pres enilin in mediating the ligand-induced transmembrane cleavage.