Regulation of cell shape by the canonical Wnt pathway

Epithelial morphogenesis is driven by coordinated cell shape changes that rely on rearrangements of the cytoskeleton. Signal transduction pathways function upstream of morphogenesis, but the molecular connections between signaling and cytoskeletal dynamics are not well understood. The canonical Wnt pathway has well known roles in specifying cell fate during development, but much less is known about its role in morphogenesis. The tumor suppressor Adenomatous polyposis coli (APC) is a negative regulator of Wnt signaling and functions in cytoskeletal organization. To determine the consequences of complete loss of APC function in a model epithelium, we generated APC2 APC1 double null clones in the Drosophila wing imaginal disc. We show that APC loss leads to cell segregation, apical constriction, and invagination that result from activation of Wnt signaling. Wnt activation is reported to upregulate DE-cadherin in wing discs. We find that apical constriction and invagination of APC null tissue are independent of DE-cadherin upregulation, but are dependent on Myosin II activity. Further, we show that the Rho1 activator RhoGEF2 is enriched in apically constricting APC mutant cells, and that dominant negative Rho1 disrupts apical constriction and invagination. Our data provide evidence for a novel link between canonical Wnt signaling and tissue morphogenesis through activation of the Rho1 pathway and Myosin II in the wing imaginal disc. Because early development of mouse intestinal polyps initiates with an invagination of APC mutant tissue, our findings contribute to understanding the molecular basis of both normal morphogenesis and polyposis.