The role of Fat in achieving signaling robustness and fidelity during the determination of planar cell polarity in the Drosophila wing.

摘要

Epithelial cells are polarized not only along their apical-basal axis, but also within the plane of the epithelia. Such polarization is termed planar cell polarity (PCP). Previous studies in Drosophila framed a PCP signaling paradigm that involves multiple tiers of regulation. Two non-classical cadherins, Dachsous (Ds) and Fat (Ft), and a type II transmembrane protein Four-jointed (Fj) provide all the cells with a directional polarizing cue with respect to the tissue axes, making each cell poised to polarize; A group of "core" PCP molecules, such as Frizzled (Fz), Dishevelled (Dsh) and Prickle (Pk), form an intercellular feedback loop that coordinates the PCP of each cell with that of its neighbor, and propagates PCP across a field of cells.; In this thesis work, I first characterize the interactions among Fj, Ds and Ft that may be important in establishing global asymmetry. I also show that cooperation between the directional information mediated by Ft, and the local alignment feedback mechanism coordinated by Frizzled (Fz) achieves high signaling fidelity. In the absence of Ft, the feedback loop is robust enough to sometimes mitigate the impact of loss of global signal in short range by locally aligning PCP, thus preventing errors from occurring and maintaining correct PCP readout in ft mutant clones.; Next, in collaboration with Keith Amonlidviman in Claire Tomlin's group, we investigate what factors impel the PCP mechanism to be robust. We show that normal developmental irregularities, such as vein formation and irregular cell-cell packing, can impede PCP propagation. Using genetic analyses and mathematical modeling, we demonstrate that the irregularities associated with normal cytoskeletal rearrangements are obstacles for the PCP signaling network to overcome. Removing Ft function reveals the inherent geometry dependence of the Fz feedback loop. Hence, the global asymmetry signal mediated by Ft needs to be broadly distributed across the tissue, so that it assists the feedback loop to overcome the geometry dependence. Consequently, the cooperation between the global directional cue and the feedback loop constructs a robust PCP signaling system that not only achieves signaling fidelity, but also maintains phenotypic stability in the presence of errors and perturbations.