Integrins regulate epithelial cell differentiation by modulating Notch activity

Coordinating exit from the cell cycle with differentiation is crucial for proper development and tissue homeostasis. Failure to do so can lead to aberrant organogenesis and tumorigenesis. However, little is known about the developmental signals that regulate the switch from cell cycle exit to differentiation. Signals downstream of two key developmental pathways, Notch and Salvador-Warts-Hippo (SWH), and signals downstream of myosin activity regulate this switch during the development of the follicle cell epithelium of the Drosophila ovary. Here, we have identified a fourth player, the integrin signaling pathway. Elimination of integrin function blocks the mitosis-to-endocycle switch and differentiation in posterior follicle cells (PFCs), by regulation of the cyclin-dependent kinase inhibitor (CKI) dacapo. In addition, integrin-mutant PFCs show defective Notch signaling and endocytosis. Furthermore, integrins act in PFCs by modulating the activity of the Notch pathway, as reducing the amount of Hairless, the major antagonist of Notch, or misexpressing Notch intracellular domain rescues the cell cycle and differentiation defects. Taken together, our findings reveal a direct involvement of integrin signaling on the spatial and temporal regulation of epithelial cell differentiation during development.