Coupling mathematical modeling with a novel human intestinal stem cell system to understand feedback regulation during planar cell polarity.

The Planar Cell Polarity (PCP) complex regulates many diverse phenotypes. While recent literature has elucidated key mechanisms underlying PCP, a mechanistic understanding of how these components function as a system to drive polarity is lacking. Here, we develop a comprehensive multicellular mathematical model centered around key PCP phosphorylation events, directly simulating the protein interactions that drive PCP. Our model confirms key PCP phenotypes, including robust single-junction asymmetry and multicellular polarity alignment in the absence of extrinsic signals. It predicts unique roles for the two known positive feedback mechanisms and predicts that VANGL-mediated DVL phosphorylation may be an underappreciated negative feedback mechanism. To test model predictions, we employ transgenic primary human intestinal epithelium cultured on biomimetic planar-crypt microarrays (PCMs) as a new platform for studying PCP. Together, our model provides novel insights into the mechanisms that regulate PCP, while our experimental results highlight an unappreciated role for PCP in intestinal biology.