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Planar cell polarity (PCP) signaling generates subcellular asymmetry along an axis orthogonal to the epithelial apical-basal axis. Through a poorly understood mechanism, cell clones that have mutations in some PCP signaling components, including some, but not all, alleles of the receptor frizzled, cause polarity disruptions of neighboring wild-type cells, a phenomenon referred to as domineering nonautonomy. Here, a contact-dependent signaling hypothesis, derived from experimental results, is shown by reaction-diffusion, partial differential equation modeling and simulation to fully reproduce PCP phenotypes, including domineering nonautonomy, in the Drosophila wing. The sufficiency of this model and the experimental validation of model predictions reveal how specific protein-protein interactions produce autonomy or domineering nonautonomy.
As the understanding of cellular regulatory networks grows, system behaviors resulting from feedback effects have proven sufficiently complex so as to preclude intuitive understanding. The challenge now is to show that enough of a network is understood to explain such behaviors. Using mathematical modeling, we show the sufficiency of a proposed biological model and study its properties, to demonstrate that it can explain complex PCP phenotypes and to provide insight into the system dynamics that govern them.
Many epithelia are polarized along an axis orthogonal to the apical-basal axis. On the Drosophila adult cuticle, each hexagonally packed cell elaborates an actin-rich hair that develops from the distal vertex and points distally (Fig. 1A). Genetic analyses have identified a group of PCP proteins whose activities are required to correctly polarize these arrays (1, 2). The domineering nonautonomy adjacent to cell clones mutant for some, but not other, PCP genes has not yet been adequately explained (1). For example, in the Drosophila wing, Van Gogh/strabismus (Vang; encoding a four-pass transmembrane protein) (3, 4) clones disrupt polarity proximal to the mutant tissue (3), whereas null frizzled (fz; encoding a seven-pass transmembrane protein) alleles disrupt polarity distal to the clone (5, 6). Models to explain this phenomenon have often invoked diffusible factors, referred to as factor X or Z, because they have not yet been identified (1, 7-15). We propose instead that the observed behaviors of known PCP proteins are sufficient to explain domineering nonautonomy.
Fz and other PCP signaling components accumulate selectively on the distal or proximal side of wing cells (Fig. 1A). Evidence has been provided that...