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

Abstract

The lungs enable the exchange of gases between inhaled air and the bloodstream. This exchange happens in structures called alveoli, which have a large surface area that aids in efficient gas exchange. Shortly after birth in mice, or during the last few months before birth in humans, alveoli develop folds called secondary septa that increase their surface area and improve the efficiency of gas exchange. Several types of cells work together to form secondary septa. Surface cells called epithelia and underlying “myofibroblast” cells and small blood vessels must both communicate and move together to build the septa. The processes that control the formation of septa have not been fully studied. In other cases, a cell signaling pathway known as the planar cell polarity (PCP) pathway has been shown to help coordinate cell movements. The PCP pathway works by changing the cytoskeleton of cells, which is the series of protein fibers that give cells their shape and structure and the ability to move. Zhang et al. have now studied septa in mouse lungs and revealed how three genes – Wnt5a, Ror2 and Vangl2 – in the PCP pathway control this process. This pathway oversees changes to the cytoskeleton in both epithelial cells and myofibroblasts, helping the cells to change shape and move together to form septa. Unusually, the PCP pathway has different effects in different cells, rather than affecting all cells similarly. This is partly due to so-called PDGF signals from the epithelial cells that help to guide the growth and movement of myofibroblasts. This process is helped by the epithelial cells changing their shape to accommodate myofibroblasts during septa formation. Further analysis also showed reduced PCP signaling in patients with chronic obstructive pulmonary disease, also known as COPD. This could be a factor in the extensive lung damage seen in these patients. These findings help to explain a key lung development process and may provide new insights to understand lung diseases such as COPD.