Heterozygous Vangl2 Looptail mice reveal novel roles for the planar cell polarity pathway in adult lung homeostasis and repair

Abstract

Lung diseases impose a huge economic and health burden worldwide. A key aspect of several adult lung diseases, such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), including emphysema, is aberrant tissue repair, which leads to an accumulation of damage and impaired respiratory function. Currently, there are few effective treatments available for these diseases and their incidence is rising. The planar cell polarity (PCP) pathway is critical for the embryonic development of many organs, including kidney and lung. We have previously shown that perturbation of the PCP pathway impairs tissue morphogenesis, which disrupts the number and shape of epithelial tubes formed within these organs during embryogenesis. However, very little is known about the role of the PCP pathway beyond birth, partly because of the perinatal lethality of many PCP mouse mutant lines. Here, we investigate heterozygous Looptail (Lp) mice, in which a single copy of the core PCP gene, Vangl2, is disrupted. We show that these mice are viable but display severe airspace enlargement and impaired adult lung function. Underlying these defects, we find that Vangl2Lp/+ lungs exhibit altered distribution of actin microfilaments and abnormal regulation of the actin-modifying protein cofilin. In addition, we show that Vangl2Lp/+ lungs exhibit many of the hallmarks of tissue damage, including an altered macrophage population, abnormal elastin deposition and elevated levels of the elastin-modifying enzyme, Mmp12, all of which are observed in emphysema. In vitro, disruption of VANGL2 impairs directed cell migration and reduces the rate of repair following scratch wounding of human alveolar epithelial cells. Moreover, using population data from a birth cohort of young adults, all aged 31, we found evidence of an interactive effect between VANGL2 and smoking on lung function. Finally, we show that PCP genes VANGL2 and SCRIB are significantly downregulated in lung tissue from patients with emphysema. Our data reveal an important novel role for the PCP pathway in adult lung homeostasis and repair and shed new light on the genetic factors which may modify destructive lung diseases such as emphysema.

Noncanonical Wnt planar cell polarity signaling in lung development and disease

“…PCP and noncanonical Wnt signaling has been shown to play a central role in the disruption of alveolar homeostasis and the maladaptive endogenous tissue regeneration response that underlies this disease [1]. While Vangl2 homozygous lethal mutant mice contain lungs with severe developmental morphogenetic defects [36], the lungs of the viable heterozygous animals exhibit many of the hallmarks of tissue damage reminiscent of emphysema [13]. These include an abnormal macrophage profile and elevated levels of elastin and the Mmp12 elastin-modifying enzyme.…”

“…These include an abnormal macrophage profile and elevated levels of elastin and the Mmp12 elastin-modifying enzyme. The expression of VANGL2 and its binding partner SCRIB are also down-regulated in emphysematous human lungs [13]. VANGL2 disruption leads to impaired directional migration and delayed wound repair via disrupted actin dynamics in a human alveolar epithelial cell line, a defect shared with PCP mutant airway [88] epithelial cells [12].…”

“…PCP is best known as a developmental regulator of polarized tissue morphogenesis involved in the hair follicle and cochlear hair cell orientation and convergent extension during neural tube closure [9][10][11]. However, it also carries out homeostatic roles in adult organs, including the lung [12,13] and is accordingly involved in diseases affecting these tissues [14]. The most completely elucidated PCP signaling mechanism is for its namesake processthe polarization of cells along the proximal-distal plane of an epithelial sheet, orthogonal to their apical-basal axis ( Figure 1B).…”

Non-canonical Wnt signalling initiates scarring in biliary disease

“…A small number of studies have demonstrated that non--canonical Wnt signalling plays a role in post-natal organ growth (23)(24)(25) and in cancer (26)(27)(28). These studies have shown that, in the adult, non-canonical Wnt components are involved in the activation of cJun N--terminal kinase (JNK) (17), regulation of matrix--metalloproteinase--14 (29), activation of integrin αv (30) and promotion of epithelial polarity (25). Moreover, a small number of reports have indicated that non--canonical Wnt signalling, through Vangl2, regulates the extra--cellular matrix in vivo (4,25,31).…”

“…These studies have shown that, in the adult, non-canonical Wnt components are involved in the activation of cJun N--terminal kinase (JNK) (17), regulation of matrix--metalloproteinase--14 (29), activation of integrin αv (30) and promotion of epithelial polarity (25). Moreover, a small number of reports have indicated that non--canonical Wnt signalling, through Vangl2, regulates the extra--cellular matrix in vivo (4,25,31). However, it remains unclear what the core function of non--canonical Wnt signalling is in the adult liver.…”