Long-range coordination of planar polarity - Project Summary The highly conserved Planar Cell Polarity (PCP) pathway is essential for cells to communicate directional information between neighboring cells to drive collective cell movements and oriented cell behaviors during embryonic development. Disruptions in PCP signaling lead to severe developmental disorders including congenital heart defects, neural tube closure defects, and shortened body axes. The core PCP proteins are transmembrane proteins that asymmetrically polarize to opposite sides of the cell. Extracellularly, the proteins form an asymmetric bridge that directly couples the polarity of one cell to its adjacent neighbors. In this way, the PCP proteins self-organize to coordinate cell polarity at the local level. A hallmark of PCP polarity, however, is its tissue-wide coordination, spanning hundreds or thousands of cells across great distances. The self-organizing properties of the core pathway alone cannot account for this long-range coordination as self-organization could occur spontaneously in any direction. Further, modeling has shown that self-organization can only propagate locally, resulting in a swirling pattern of PCP polarity rather than tissue-level coordination. For this reason, the PCP field has come to a consensus that ‘directional cues’ are key missing factors that must link the PCP axis to the tissue axis. Directional cues are thought to act in a gradient across a tissue where they bias the distribution of the PCP proteins along the same axis by regulating their trafficking, stability, or turnover. Despite a general consensus on how directional cues could pattern PCP organization, the identities of these cues remain elusive. As such, the mechanism of their action cannot be interrogated. A major challenge in identifying directional cues is that they are also required for tissue growth and differentiation. Thus, the tissue of interest becomes compromised in the absence of the cue, making it difficult to investigate the cue’s role in organizing PCP in isolation. Epidermal tissues provide a striking readout of planar polarity in their uniform alignment of bristles, scales, fur, and feathers across an animal’s body. Remarkably, spontaneous mutations in small mammals and birds have produced animals with region-specific misorientation of epidermal polarity. From these phenotypes, we hypothesize that the skin is compartmentalized into region-specific domains that require multiple directional cues to coordinate polarity across the tissue. Further, the fact that the skin is morphologically normal under these conditions despite the polarity defects demonstrates that the skin can be leveraged as a model system to interrogate directional cues. Our long-term goal is to identify and study the directional cues that pattern PCP across the mouse epidermis to reveal mechanisms that coordinate long-range polarity. By using natural variants and taking a candidate approach, we will identify and characterize directional cues and will reveal how they alter the dynamics of PCP asymmetry along a tissue axis. This approach addresses critical and long-standing questions in the PCP field and will shed light on fundamental mechanisms that pattern embryonic tissues.
