Regulation of tissue growth and morphogenesis by Fat cadherins

Regulation of Tissue Growth and Morphogenesis by Fat Cadherins Project Summary Formation of optimally functioning organs of appropriate size and shape requires precise coordination of growth and morphogenesis during development. The evolutionarily conserved cell adhesion molecules Dachsous and Fat coordinately regulate tissue growth and patterning by influencing Hippo signaling and planar cell polarity respectively. Mutations in these genes give rise to devastating Van Maldergem and Hennekam syndromes characterized by congenital developmental defects of multiple organ systems. Further, mutations in these genes are also implicated in several cancers. However, there are critical gaps in our understanding of how they regulate growth and morphogenetic processes. We know little about how the spatial organization of the pathway is established and maintained and how the Ds-Fat junctions get coordinately remodeled to allow morphogenesis. Further, we lack a coherent view of how this pathway regulates Hippo signaling. Lastly, it is not clear how Fat regulates organ shape. To address these critical gaps, we will use the fruit fly Drosophila, which provides a robust model system to study this pathway. Our recent work has identified several novel regulators of this pathway and uncovered some intriguing findings, which suggest that vesicular trafficking provides an important layer of regulation in organization of the Fat signaling pathway, an aspect that has been overlooked so far. We will investigate how an intricate interplay between the endocytic machinery and a competitive inhibitor plays a critical role in organization of this pathway. Further, we will investigate how the Ds-Fat junctions get remodeled by endocytosis in a mechanosensitive manner to allow morphogenesis. We have identified a key regulatory motif in the Fat cytoplasmic domain and its interactors, which play an important role in Fat recycling to the plasma membrane. We will characterize how this motif regulates Fat localization at the plasma membrane. Additionally, we will investigate how Fat regulates Hippo signaling through the atypical myosin Dachs. Finally, we will examine how Fat signaling affects the key morphogen gradients and conduct live imaging combined with quantitative image analysis to identify the key cellular rearrangements that mediate organ shape alterations in Fat mutants. These studies will 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.