View Program - 63rd Annual Drosophila Research Conference

Proper coordination of growth and morphogenesis during development is critical to formation of appropriately proportioned organs. The evolutionarily conserved protocadherins, Dachsous (Ds) and Fat constitute a signaling pathway that coordinates growth and morphogenesis by regulating the Hippo pathway and planar cell polarity (PCP) respectively. However, there are critical gaps in our understanding of how they regulate growth and morphogenetic processes. Further, little is known about how the spatial organization of the pathway is established and maintained and how the Ds-Fat junctions get coordinately remodeled along with other adhesion complexes to allow morphogenesis. To address these critical gaps, we use the Drosophila wing disc which provides a robust model system to study this pathway. In the developing Drosophila wing disc epithelium, Ds is expressed in a steep gradient with high expression from the periphery to the very low expression at the center of the wing pouch. In contrast, Fat is mostly expressed uniformly. The interaction between Ds and Fat is modulated by phosphorylation by the Golgi-resident kinase Four-jointed, which is expressed in an opposing decreasing gradient from the center to the periphery. The graded expression of Ds and Fj along with uniform expression of Fat results in an increasing gradient of Fat activity from the center to the periphery and slope of the gradient of Fat activity regulates cell proliferation by influencing Hippo signaling pathway. Membrane localization of Fat and Ds is dynamically regulated, where unliganded Fat is rapidly endocytosed, compared to the liganded population. Given that Ds level is very low at the center of the pouch region, most of the Fat should be unliganded and unstable. Therefore, there must be a mechanism to protect the unliganded Fat from endocytic turnover. We have identified a critical motif in the Fat cytoplasmic domain that bind to a key endocytic adapter and also have identified that the Lix1 homolog Low Fat competitively inhibit Fat endocytosis. Further, we have identified that an intricate interplay between recycling and endocytosis plays a central role in maintaining Fat levels. Taken together, these results indicate that vesicular trafficking provides an important layer of regulation in organization of the Fat signaling pathway, an aspect that has been overlooked so far. Furthermore, these studies provide novel mechanistic insight into Fat signaling pathway and address several longstanding questions in the field and will help explain the developmental disorders resulting from dysregulation of this pathway.

Endocytic regulation of Fat protocadherins in tissue growth and morphogenesis