Modeling the control of planar cell polarity

Abstract

A growing list of medically important developmental defects and disease mechanisms can be traced to disruption of the planar cell polarity (PCP) pathway. The PCP system polarizes cells in epithelial sheets along an axis orthogonal to their apical-basal axis. Studies in the fruitfly, Drosophila, have suggested that components of the PCP signaling system function in distinct modules, and that these modules and the effector systems with which they interact function together to produce emergent patterns. Experimental methods allow the manipulation of individual PCP signaling molecules in specified groups of cells; these interventions not only perturb the polarization of the targeted cells at a subcellular level, but also perturb patterns of polarity at the multicellular level, often affecting nearby cells in characteristic ways. These kinds of experiments should, in principle, allow one to infer the architecture of the PCP signaling system, but the relationships between molecular interactions and tissue-level pattern are sufficiently complex that they defy intuitive understanding. Mathematical modeling has been an important tool to address these problems. This article explores the emergence of a local signaling hypothesis, and describes how a local intercellular signal, coupled with a directional cue, can give rise to global pattern. We will discuss the critical role mathematical modeling has played in guiding and interpreting experimental results, and speculate about future roles for mathematical modeling of PCP. Mathematical models at varying levels of inhibition have and are expected to continue contributing in distinct ways to understanding the regulation of PCP signaling.