Drosophila ERM protein moesin functions in epithelial integrity and cell survival

A dynamic organization of cortical actin filaments and their interactions with the plasma membrane are important for many membrane-based biological processes, such as cell adhesion, cytokinesis, cell shape maintenance, and motility. Ezrin, Radixin, and Moesin (ERM), a group of closely related proteins within the Protein 4.1 superfamily, are thought to play a structural role in the formation of actin-based cell surface structures that are necessary for these processes. Because of their ability to associate with integral membrane proteins and actin filaments, the ERM proteins have been proposed to work as cross-linkers between the cortical cytoskeleton and the plasma membrane. Other studies have shown that the ERM proteins have the ability to induce global changes in the cellular cytoskeleton and the state of cell polarization, suggesting an involvement in signal transduction pathways. Genetic analyses that could test hypotheses regarding the ERM proteins' involvement in cytoskeletal support and signaling have been impeded by functional redundancies between these three proteins in mammals. In contrast, Drosophila has only one ERM gene, Moesin, enabling an in vivo genetic analysis of ERM function. To study the function of Drosophila Moesin, several loss-of-function Moesin alleles were isolated. Phenotypic analysis of these alleles shows that Moesin promotes cortical actin assembly and apical-basal polarity in epithelial cells. Moesin is also required for epithelial cell survival. Loss of Moesin function results in depletion of filamentous actin in the apical domain and basal extrusion of cells from the epithelial monolayer in the wing imaginal disc. Strikingly similar phenotypes are observed when the function of the small GTPase Rho is upregulated in epithelial cells. Genetic interactions with Rho and Rho pathway components show that Moesin facilitates epithelial morphology not by cross-linking the plasma membrane to the cytoskeleton, but rather by antagonizing Rho pathway activity. Additionally, Moesin mutant cells extruded from the epithelium undergo apoptosis via the activation of the JNK signaling pathway. Thus, the mechanism of ERM function in maintaining epithelial integrity is by regulation of cell-signaling events that affect actin organization, epithelial cell morphology, and cell survival.