Epithelial cell shape changes during lung branching morphogenesis: The role of Wnt/Fzd2 signaling in directing new branch formation

Formation of the intricately branched mammalian lung requires precise coordination between the epithelium and mesenchyme over the course of development. This coordination is mediated by molecular signaling between the two tissue compartments. How these signaling pathways coordinate changes in cellular and tissue morphology to give rise to the highly ramified branched network of the lung is not well understood. In this work, I show that signaling through Frizzled 2 (Fzd2) is required for promoting changes in epithelial cell shape that lead to tissue-level changes needed for branching morphogenesis in the lung. Through analysis of both fixed lungs and live imaging lung explants, I was able to identify the changes in individual cell morphology and epithelial tissue organization that occur during new domain branch formation. Using this model, I characterized the defect in branching morphogenesis that arises due to loss of Fzd2 in the lung epithelium. I found that Fzd2 affects apical localization of phospho-myosin light chain 2, and through the RhoA pathway mediates changes in cell shape that lead to thickening of the lung epithelium and ultimately bending of the epithelium. These studies provide a mechanistic link between the Wnt signaling pathway and changes in cell morphology that lead to branching morphogenesis of the lung epithelium