Non-canonical WNT signalling in the lung

Abstract

The role of WNT signalling in metazoan organogenesis has been a topic of widespread interest. In the lung, while the role of canonical WNT signalling has been examined in some detail by multiple studies, the non-canonical WNT signalling has received limited attention. Reliable evidence shows that this important signalling mechanism constitutes a major regulatory pathway in lung development. In addition, accumulating evidence has also shown that the non-canonical WNT pathway is critical for maintaining lung homeostasis and that aberrant activation of this pathway may underlie several debilitating lung diseases. Functional analyses have further revealed that the non-canonical WNT pathway regulates multiple cellular activities in the lung that are dependent on the specific cellular context. In most cell types, non-canonical WNT signalling regulates canonical WNT activity, which is also critical for many aspects of lung biology. This review will summarize what is currently known about the role of non-canonical WNT signalling in lung development, homeostasis and pathogenesis of disease.

Keywords: WNT; development; lung; non-canonical.

Fig. 1

Illustration of major cell types in late stage developing lungs. (A) Gross morphology of E18 trachea and lungs. (B, C) H&E staining of sectioned E18 trachea and mainstem-bronchi and lungs, respectively. (D) Basal cells (green, TRP63 staining) in E18 trachea. Lateral membranes of the epithelial cells were labelled by β-catenin (red). (E) Club cells (red, SCGB1A1 staining) and ciliated cells (green, β4-tubulin staining). (F) NECs (red, UCHL1 staining) in E18 intralobular airways. (G, H) Airway SMC and vascular SMC (green, ACTA2 staining), respectively, in E18 lungs. Endothelial cells in (H) were labelled by CD31 (red). Structure of the E18 distal airspace (saccules) is shown as inset in (A). By PN11, the distal lung develops and forms alveoli (I). (J–L) Distribution of AT2 (green, SPC staining), AMF (green, ACTA2 staining) and endothelial cells (green, endomucin staining) in relation to AT1 cells (red, PDPN staining) in PN11 alveoli. (M) Distribution of lipofibroblasts (red, oil-red-O staining) and AMFs (green, labelled by GFP) in PN11 Gli1-cre^ERT2;ROSA^mTmG lungs (5). Nucleus (blue) was visualized by Dapi staining in immunofluorescent staining.

Fig. 2

Multiplicity of non-canonical WNT pathways and their identified functions in the lung. Binding of WNT ligands to individual or different combination of their receptors including FZD, ROR1, ROR2 or RYK activates multiple β-catenin-independent pathways. Amongst these, the PCP pathway and Ca²⁺ pathway are the most studied and have been found to regulate multiple functions in the lung. Details of each intracellular pathway are not shown as they have been illustrated by previous reviews (28, 35, 36, 37). BEC, bronchial epithelial cell; SMC, smooth muscle cell; ECM, extracellular matrix; AT2, type 2 AEC.

Fig. 3

Ror deficiency blocks Wnt5a function in developing lungs. Shows E18 wild-type control (Ctrl, A), Spc-Wnt5a transgenic (Tg, C), Ror1^−/−- ;Ror2^−/− (wko, B) and SpC-Wnt5a;Ror1^−/− ;Ror2^−/− (tTg, D) lungs. Overexpression of Wnt5a disrupted lung development, represented by missing accessory lobe (dashed line, C) and fusion of right lobes (C versus A). However, overexpression of Wnt5a in Ror1^−/− ;Ror2^−/− genetic background (tTg) did not lead to a similar phenotype as Spc-Wnt5a transgenic lungs (D versus C). The morphology of the tTg lungs is similar to Ror1^−/− ;Ror2^−/− wko lungs (D versus B). Accessory lobes are shown by dashed lines in (A, B, D).