7. Abstract One of biology’s central challenges to define the mechanisms by which the single cell zygote assembles itself into the complex body plan of an animal. For the last 27 years we have addressed this fundamental question, following the lead initially provided by the dual functions of bcatenin in cell adhesion and Wnt signaling. We seek to determine how cells assemble polarized tissues and organs and change shape and move during morphogenesis, by coordinating cell adhesion and the cytoskeleton. In parallel, we study Wnt signaling, a paradigm for mechanisms cells use to choose and maintain fate in development and homeostasis and how this goes wrong in disease. We study these events in Drosophila, using its sophisticated genetic tools along with cutting edge microscopy to explore events in vivo, and combine this with work in cultured mammalian cells, to explore conservation and divergence of these mechanisms. Many of the proteins on which we focus are disrupted in human developmental disorders, cancer initiation and metastasis. Currently we explore three key questions in the field. First, we ask how cells initiate and maintain apical-basal polarity, a fundamental property of animal tissues. Cell-cell adherens junctions serve as key polarity landmarks, demarcating the apical and basolateral domains. Our goal is to determine how different upstream inputs are integrated to position adherens junctions during apical-basal polarity establishment, and to define mechanisms ensuring robust polarity maintenance. We hypothesize that the egg plasma membrane and the polarized cytoskeleton it organizes act through multiple effectors to position adherens junctions, with junctional proteins acting as coincidence detectors, and that new mechanisms turn on at gastrulation onset, buffering errors during cellularization. Second, we explore mechanisms by which cell-cell junctions link to the actomyosin cytoskeleton to allow cell shape change without disrupting epithelial integrity. We hypothesize different cells choose from an array of proteins/protein complexes to assemble and link adherens junctions, with different proteins contributing distinct dynamics or force resistance, and that multivalent interactions among the proteins increases robustness. In parallel, we ask how upstream signaling cues drive integrated cytoskeletal responses in morphogenesis, using Abl kinase as a model. Third, we explore how cells choose and maintain fate, using Wnt signaling as a model. We focus on the tumor suppressor Adenomatous polyposis coli (APC), a key negative regulator that is mutated in 80% of colon cancers. Our long-term goal is to determine how APC and its partners in the Wnt-regulatory destruction complex regulate signaling during development and homeostasis, and how that goes wrong in cancer. We hypothesize that the destruction complex is a multimeric machine assembled by polyvalent interactions, that its cellular localization and assembly state are regulated by Wnt si...