Cell-cell interactions in drosophila development

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The development of a multicellular organism requires the commitment of individual cells to the appropriate cell fate and then their subsequent differentiation. One of the key pathways involved in specifying cell fates in organisms as diverse as worms to man, is the Notch signaling pathway. A key component of this pathway is Neuralized, which we identified many years ago. During the course of our previous NSERC grant, we showed that Neuralized encodes an E3-ubiquitin ligase that targets the Notch ligand, Delta, for ubiquitin-mediated internalization. This provided the first evidence that intracellular trafficking of its ligands could regulate the Notch pathway. We also demonstrated that Neuralized binds to phosphoinositides, membrane lipids that mediate membrane trafficking and signaling. Moreover, we showed that the interaction between Neuralized and phosphoinositides was required for Delta internalization and the initiation of Notch signaling. The goal of the present proposal is to determine if phosphorylation can regulate the interaction of Neuralized with phosphoinositides. We will also determine if the interaction between Neuralized and phosphoinositides is required for other aspects of Notch signaling. Finally, we will determine how protein-protein interactions affect the ability of Neuralized to bind and endocytose Delta and whether these are required for other developmental processes. These studies will help us to elucidate the function of Neuralized in cell fate decisions and its relationship to known signaling pathways important in regulating cell-cell interactions during development. Since Neuralized and the Notch pathway are highly conserved, understanding the function of these genes in Drosophila will also shed light onto ways that cell fates are acquired in most multicellular organisms. Finally, understanding the mechanisms regulating cell-cell interactions in development may provide insights into defects in cell fate decisions and in cell-cell signaling associated with human diseases such as cancer.