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

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.