On the Long-Range Coordination of Epidermal Planar Cell Polarit

Planar cell polarity (PCP) refers to the collective alignment of cells or groups of cells within the epithelial plane. The establishment of PCP requires an asymmetric distribution of core PCP complexes within each cell across the tissue plane, and this asymmetry functions to inform downstream polarized cellular behaviors such as directed cell migration, unidirectional cilia beating, and oriented cell divisions. While significant progress has been made towards understanding the mechanisms controlling the asymmetric molecular interactions between core PCP complexes, less is known about the global inputs that direct and align this asymmetric protein localization patterns over long distances, especially in vertebrate systems. In this thesis, we explore the mechanisms governing the asymmetric distribution of a core PCP protein, Celsr1 in mammalian skin. We demonstrate that the onset of Celsr1 asymmetry coincides both temporally and spatially with a gradient of tissue deformation oriented along the medial-lateral axis across the back skin. We present evidence that uniaxial tissue strain can act as a long-range polarizing cue for reorienting Celsr1 polarity. Observations both in vivo and in vitro suggest that the effect of tissue anisotropy on Celsr1 polarity is not a direct consequence of cell shape but rather reflects the restructuring of cell-cell interfaces during oriented cell divisions and cell rearrangements that serve to relax tissue strain. Using a clonal analysis approach, we demonstrate that cell intercalations remodel intercellular junctions predominantly between the mediolateral interfaces of neighboring cells. This restructuring of the cell surface polarizes Celsr1, which is slow to accumulate at nascent junctions yet stably associates with persistent junctions. Together, these results demonstrate that tissue anisotropy globally aligns Celsr1 polarity by creating a directional bias in the formation of new cell interfaces while simultaneously restricting Celsr1 along persistent anterior-posterior interfaces.