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.

The Planar Polarity Component VANGL2 Is a Key Regulator of Mechanosignaling

“…WNT5A is a current target of interest for treatment of several lung diseases in which there is aberrant expression of this ligand including: chronic obstructive pulmonary disease (COPD)/emphysema, idiopathic pulmonary arterial hypertension (IPAH), bronchopulmonary dysplasia (BPD), and interstitial pneumonia (UIP) (Vuga et al, 2009;Baarsma et al, 2017;Yuan et al, 2019;Li et al, 2020;Sucre et al, 2020;Vladar and Königshoff, 2020). In addition, WNT5A has an important role in progenitor cell induction following lung injury (Nabhan et al, 2018).…”

Primary Cilia and Calcium Signaling Interactions

“…In some mammalian cells, one of the early signs of planar cell polarity is the establishment of the cilia on the apical side of the cell [ 86 ]. Many pathways involved in cell migration have been associated with primary cilia such as Hh, Wnt, and transforming growth factor beta (TGFβ) [ 87 , 88 , 89 , 90 ]. Cellular polarization is necessary to coordinate directional migration and can also do so through the multifaceted role of Ca 2+ .…”

“…Thus, cell polarity is essential for proper asymmetric divisions, leading to neurogenesis, neuronal positioning, and cellular differentiation [ 93 , 94 ]. Many of the driving pathways of neurogenesis, such as Notch, Hh, and Wnt, have been directly connected to primary cilia [ 89 , 95 , 96 , 97 , 98 , 99 ]. While the phenotypes in ciliopathies are often heterogeneous, there are common pleiotropic features that include brain malformations and neurological impairment; although specifics vary in frequency and phenotype depending on the ciliopathy in question [ 100 ].…”

The Role of Notch and Wnt Signaling in MSC Communication in Normal and Leukemic Bone Marrow Niche

“…Core components on the distal membrane consist in Frizzled and the scaffold partners Dvl, Diego and Flamingo. The counterpart on the proximal membrane involved Van Gogh, Prickle, and Flamingo scaffolds (Vladar and Königshoff, 2020). Although the two complexes are interconnected, a simple presentation of the signal transduction after ligand binding on Frizzled receptors shows the recruitment FIGURE 2 | Wnt signaling, structure and activation: Wnt signaling is activated when glycoprotein ligands of the Wnt family bind Frizzled transmembrane receptors located at cell membrane level.…”

“…of Dvl, Diego and Flamingo and the formation of a protein platform triggering the activity of Rho family GTPase proteins to regulate actin organization and cytoskeleton dynamics (Figure 2; Siar et al, 2012;Vladar and Königshoff, 2020). Another wellknown β-catenin-independent pathway is the Wnt/Ca 2+ , which controls the levels of intracellular Ca 2+ (Figure 2).…”