Ciliary orientation by planar cell polarity (PCP) signaling
PCP is best understood in Drosophila, where it acts via: 1. global cues that define the proximal-distal (P-D) tissue axis, 2. intercellular signaling that aligns neighboring cells with each other along the tissue axis, and 3. intracellular cytoskeletal dynamics that polarize cellular structures. Intercellular signaling is mediated by asymmetrically distributed PCP proteins at the P-D side apical junctions of cells (termed “crescents”), and the orientation of crescents is determined by global cues. PCP is conserved, but mechanisms are not well understood in vertebrates. It drives directional cell behaviors in neurulation, epithelial tubulogenesis, axon guidance and hair follicle orientation, and it is linked to developmental defects and disease. We demonstrated that the PCP signaling pathway physically orients cilia for directional motility for mucociliary clearance. We discovered that an intercellular communication mechanism orients cells with respect to the tissue axis in the airway epithelium prior to ciliogenesis and that within MCCs cilia are oriented by microtubules that tether them to a region of the cell cortex specified by PCP proteins. This was the first vertebrate PCP mechanism described, and it lays the foundation for careful dissection of the pathway, including the identification of the long-sought global cues for the tissue-wide coordination of polarity. We use mouse mutants and primary cell culture to study the three tiers of PCP signaling and the connectivity between them.