Noncanonical Wnt planar cell polarity signaling in lung development and disease

Abstract

The planar cell polarity (PCP) signaling pathway is a potent developmental regulator of directional cell behaviors such as migration, asymmetric division and morphological polarization that are critical for shaping the body axis and the complex three-dimensional architecture of tissues and organs. PCP is considered a noncanonical Wnt pathway due to the involvement of Wnt ligands and Frizzled family receptors in the absence of the beta-catenin driven gene expression observed in the canonical Wnt cascade. At the heart of the PCP mechanism are protein complexes capable of generating molecular asymmetries within cells along a tissue-wide axis that are translated into polarized actin and microtubule cytoskeletal dynamics. PCP has emerged as an important regulator of developmental, homeostatic and disease processes in the respiratory system. It acts along other signaling pathways to create the elaborately branched structure of the lung by controlling the directional protrusive movements of cells during branching morphogenesis. PCP operates in the airway epithelium to establish and maintain the orientation of respiratory cilia along the airway axis for anatomically directed mucociliary clearance. It also regulates the establishment of the pulmonary vasculature. In adult tissues, PCP dysfunction has been linked to a variety of chronic lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease, and idiopathic pulmonary arterial hypertension, stemming chiefly from the breakdown of proper tissue structure and function and aberrant cell migration during regenerative wound healing. A better understanding of these (impaired) PCP mechanisms is needed to fully harness the therapeutic opportunities of targeting PCP in chronic lung diseases.

Keywords: PCP; Wnt5a; cilia; lung; noncanonical Wnt; planar cell polarity.

Figure 1.. Canonical Wnt vs. PCP signaling pathways and the airway epithelial PCP mechanism.

(A) Schematic outline of the canonical Wnt/β-catenin and the noncanonical PCP pathways, highlighting shared and unique components and signaling outcomes. The noncanonical Wnt/PCP schematic illustrates the asymmetric localization and interaction of core PCP complexes at the apical junctions between neighboring cells. (B) A conserved PCP signaling imparts morphological polarity to Drosophila wing epithelial cells (top) and human airway epithelial cells (bottom) along the proximal-distal tissue axis through the asymmetric localization and function of the core PCP proteins, which is directly responsible for the lateral placement of wing hairs in the fly and the directional movement of cilia in the airways, respectively. (C) In individual multiciliated cells, the proximal orientation of cilia is achieved by linking the ciliary layer to the proximal side cell cortex occupied by the Fzd and Dvl core PCP proteins via PCP-regulated microtubules. In Vangl1 mutant cells the asymmetric Fzd domain fails to form and cilia do not planar polarize. Schematics of mammalian airway epithelial cells in B and C summarize findings from Vladar et al. [60].

Figure 2.. PCP regulates directional cell behaviors through polarized cytoskeletal organization.

During embryonic branching morphogenesis, PCP regulates the accumulation of actin bundles under the luminal cell surface in airway epithelial cells, as indicated by the lack of actin enrichment in Vangl2^Lp/Lp airway epithelial cell surfaces (top left). At the same time, mesenchymal cells display a polarized cortical actin network (bottom left), which is absent from Vangl2^Lp/Lp lungs, schematics adapted from Yates et al. [36]. Post-branching, PCP establishes a proximal-distal (P-D) oriented microtubule cytoskeleton under the apical cell surface in airway epithelial cells, which is responsible for the proximal directed orientation of motile cilia (top right), however in Vangl1^−/− epithelia, the microtubules are not P-D aligned, schematic adapted from Vladar et al. [60]. PCP controls the efficient directional migration of pericytes (Pc) towards pulmonary endothelial cells (En) in an in vitro assay of angiogenesis by establishing a polarized actin cytoskeleton (bottom right), as indicated by the loss of actin enrichment in pericytes depleted of FZD7 and CDC42 using RNA interference (siFZD7 + siCDC42), schematic adapted from Yuan et al. [95].