Planar polarity: A new player in both lung development and disease

Abstract

The clinical burden of both adult and neonatal lung disease worldwide is substantial; in the UK alone, respiratory disease kills one in four people. It is increasingly recognized that genes and pathways that regulate lung development, may be aberrantly activated in disease and/or reactivated as part of the lungs' intrinsic repair mechanisms. Investigating the genes and signaling pathways that regulate lung growth has led to significant insights into the pathogenesis of congenital and adult lung disease. Recently, the planar cell polarity (PCP) pathway has been shown to be required for normal lung development, and data suggests that this signaling pathway is also involved in the pathogenesis of some lung diseases. In this review, we summarize current evidence indicating that the PCP pathway is required for both lung development and disease.

Figure 1

Mutations in Celsr1 or Vangl2 cause lung morphogenesis defects. Comparison of E18.5 wild type (A), Celsr1^Crsh (B) or Vangl2^Lp (C) lung lobes; homozygous mutant lungs are misshapen. At E14.5 H&E staining of lung sections reveals that mutant airways (E and F) have narrow lumina, and the epithelium is multilayered in contrast to the wider lumina surrounded by a single layered epithelium in wild type (D). At E18.5, the width of airways in mutant lung (H and I) is dramatically reduced compared to wild-type control (G).

Figure 2

Celsr1 and Vangl2 proteins are spatially restricted and differentially expressed in lung epithelium. E14.5 transverse cryosections showing single epithelial airways immunostained with Celsr1 (A, B and E) or Vangl2 (C, D and F) antibodies. Corresponding protein levels are dramatically reduced in homozygous mutant lung tissue from Celsr1^Crsh (B) and Vangl2^Lp (D). Celsr1 expression is unaltered in Vangl2^Lp mutant lung (G), but apical enrichment of Vangl2 is lost in Celsr1^Crsh mutant lung (H).