MesenchymalVanglfacilitates airway elongation and widening independently of the planar cell polarity complex

Abstract

A hallmark of mammalian lungs is the fractal nature of the bronchial tree. In the adult, each successive generation of airways is a fraction of the size of the parental branch. This fractal structure is physiologically beneficial, as it minimizes the energy needed for breathing. Achieving this pattern likely requires precise control of airway length and diameter, as the branches of the embryonic airways initially lack the fractal scaling observed in those of the adult lung. In epithelial monolayers and tubes, directional growth can be regulated by the planar cell polarity (PCP) complex. Here, we comprehensively characterized the roles of PCP-complex components in airway initiation, elongation, and widening during branching morphogenesis of the murine lung. Using tissue-specific knockout mice, we surprisingly found that branching morphogenesis proceeds independently of PCP-component expression in the developing airway epithelium. Instead, we found a novel, Celsr1-independent role for the PCP component Vangl in the pulmonary mesenchyme. Specifically, mesenchymal loss of Vangl1/2 leads to defects in branch initiation, elongation, and widening. At the cellular level, we observe changes in the shape of smooth muscle cells that indicate a potential defect in collective mesenchymal rearrangements, which we hypothesize are necessary for lung morphogenesis. Our data thus reveal an explicit function for Vangl that is independent of the core PCP complex, suggesting a functional diversification of PCP components in vertebrate development. These data also reveal an essential role for the embryonic mesenchyme in generating the fractal structure of airways of the mature lung.

Disrupted endosomal trafficking of the Vangl-Celsr polarity complex underlies congenital anomalies in trachea-esophageal morphogenesis

“…Loss of Rab11a/b in the pancreas leads to highly disorganized epithelial defects due to the mis-localization of apical-basal proteins laminin, Par3, and aPKC, but this study did not examine whether this was due to Vangl mis-localization 37 . Interestingly, Vangl2 has a PCP-independent role in the developing lung mesenchyme during branching morphogenesis 38,39 . Neither the looptail mutation nor conditional knockout of Vangl2 using ShhCre impairs trachea-esophageal separation, however, a different Cre driver with earlier recombination in the foregut might lead to separation anomalies.…”