A mammalian Wnt5a–Ror2–Vangl2 axis controls the cytoskeleton and confers cellular properties required for alveologenesis

Alveolar formation increases the surface area for gas-exchange and is key to the physiological function of the lung. Alveolar epithelial cells, myofibroblasts and endothelial cells undergo coordinated morphogenesis to generate epithelial folds (secondary septa) within the saccules to form alveoli. A mechanistic understanding of alveologenesis remains incomplete. We found that the planar cell polarity (PCP) pathway is required in both alveolar epithelial cells and myofibroblasts for alveologenesis. Our studies uncovered a Wnt5a–Ror2–Vangl2 cascade that endows cellular properties and thus novel mechanisms of alveologenesis. This includes PDGF secretion from alveolar type I and type II cells, cell shape changes of type I cells and migration of myofibroblasts. All these cellular properties are conferred by changes in the cytoskeleton and represent a new facet of PCP function. These results extend our current model of PCP signaling from polarizing a field of epithelial cells to conferring new properties at subcellular levels to regulate collective cell behavior. Build the signal pathway axis of Ror2 - Vangl2 in lung alveolar development