Planar cell polarity mechanisms and systems architecture

Planar cell polarity (PCP) signaling controls the polarization of cells within the plane of an epithelium, orienting asymmetric cellular structures, cell divisions and cell migration. Numerous medically important developmental defects and physiological processes in vertebrates are under control of PCP signaling, motivating considerable interest in understanding the fundamental logic and underlying mechanisms controlling PCP. Major advances toward achieving this understanding have come from leveraging of genetic approaches only possible in Drosophila, and the evident conservation of mechanism reinforces the utility of flies as a model system. I propose that the next major leaps in understanding will emerge from continued innovation in genetic approaches and from expanding the reach of these approaches by employing them in cross-disciplinary studies with technologies such as single molecule imaging and advanced biochemistry. In flies, PCP signaling controls the orientation of hairs on the adult cuticle, chirality and orientation of ommatidia in the eye, orientation of cell divisions and related processes in other tissues. Several distinct molecular modules contribute to PCP signaling. The core module acts both to generate molecular asymmetry within cells and to coordinate the direction of polarization between neighboring cells. One or more global directional modules orient core polarization with respect to tissue axes, and distinct effector modules interpret core polarity to direct morphogenetic responses. A key goal has been to understand the fundamental workings of the core PCP module. Proteins in the core module segregate within cells to form distinct complexes on opposite sides of the cell, and form intercellular bridges that signal polarity between cells. The observed behavior of this module, combined with mathematical modeling, indicates that the system likely acts as a bistable switch, breaking symmetry to produce a stable, polarized array. Positive and negative feedback necessarily underlie the function of this module, but the molecular mechanisms generating feedback are as yet unknown. Furthermore, molecular-scale asymmetry in PCP is coupled to the formation of clustering of polarity components into discrete puncta, yet the precise role of clustering in polarization is not known. Our major focus going forward will be the dissection of core PCP mechanisms by developing and employing novel genetic tools and by combining these tools with single molecule imaging and advanced biochemistry to unlock an understanding of PCP signaling that previously applied experimental approaches have so far been unable to achieve. The proposed work will deliver an unprecedented view of both the fundamental logic and the precise molecular mechanisms underlying PCP signaling as well as lay the groundwork for potential therapeutic interventions for PCP related pathologies.