Mechanical forces and their molecular control during epithelial folding in Drosophila

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How form is generated is one of the big open questions in Developmental Biology. Embryos take shape by generating mechanical forces that deform epithelial sheets of cells covering the embryonic surface and inner organs. A fundamental shape change of epithelia, which takes place for example during gastrulation and the development of the eye, gut and brain, is folding. During folding, the quasi two-dimensional sheet of cells is transformed into a three-dimensional structure. A well-studied mechanism of epithelial folding is apical cell constriction. The contraction of an actomyosin network located at the apical side of cells generates mechanical forces that result in the narrowing of the apical side of cells. Coordinated apical constriction of neighboring cells results in epithelial folding. Our recent work has uncovered two additional novel mechanisms that are involved in epithelial folding. We showed by live imaging and quantitative image analysis that the formation of two neighboring folds in Drosophila wing discs, an important model system to study the development of epithelia, does not involve apical cell constriction, but rather the relaxation of the basal side of cells. In the first fold, basal relaxation correlates with a spatially defined decrease of extracellular matrix and decreased basal forces. In the second fold, basal relaxation is accompanied with a reduction in cell height that correlates with actin flows along the lateral interface between cells and increased lateral forces.The proposed work has three main aims: First, we will use optogenetics to alter force generation in cells to test whether decreased basal forces or increased lateral forces are necessary and sufficient for fold formation. Second, we will reveal how the reduction of basal force is confined to cells that form the first fold. Our preliminary data indicate that Wingless signal transduction specifies the position of this fold. We will combine force measurements with molecular genetics to test whether and how Wingless signal transduction controls basal forces. Third, we will combine live imaging with genetic analysis to decipher how actin flows are generated at the lateral side of cells and how they contribute to lateral forces. We expect that the proposed work will uncover novel principles by which mechanical forces are generated and molecularly controlled for tissues to take shape.