Vanglfacilitates mesenchymal thinning during lung sacculation independently ofCelsr

Abstract

SummaryThe planar cell polarity (PCP) complex orients cytoskeletal and multicellular organization throughout vertebrate development. PCP is speculated to function in formation of the murine lung, where branching morphogenesis generates a complex tree of tubular epithelia whose distal tips expand dramatically during sacculation in preparation for gas exchange after birth. Here, using tissue-specific knockouts, we show that the PCP complex is dispensable in the airway epithelium for sacculation. Rather, we find a novel,Celsr1-independent role for the PCP componentVanglin the pulmonary mesenchyme: loss ofVangl1/2inhibits mesenchymal thinning and expansion of the saccular epithelium. Further, loss of mesenchymalWnt5amimics the sacculation defects observed inVangl2-mutant lungs, implicating mesenchymal Wnt5a/Vangl signaling as a key regulator of late lung morphogenesis. By mathematically modeling sacculation, we predict that the process of sacculation requires a fluid mesenchymal compartment. Finally, lineage-tracing and cell-shape analyses are consistent with the pulmonary mesenchyme acting as a fluid tissue, and suggest that loss ofVangl1/2likely impacts the ability of mesenchymal cells to exchange neighbors. Our data thus uncover an explicit function forVangland the pulmonary mesenchyme during late lung morphogenesis to actively shape the saccular epithelium.