The PCP genes Celsr1 and Vangl2 are required for normal lung branching morphogenesis

Abstract

The lungs are generated by branching morphogenesis as a result of reciprocal signalling interactions between the epithelium and mesenchyme during development. Mutations that disrupt formation of either the correct number or shape of epithelial branches affect lung function. This, in turn, can lead to congenital abnormalities such as cystadenomatoid malformations, pulmonary hypertension or lung hypoplasia. Defects in lung architecture are also associated with adult lung disease, particularly in cases of idiopathic lung fibrosis. Identifying the signalling pathways which drive epithelial tube formation will likely shed light on both congenital and adult lung disease. Here we show that mutations in the planar cell polarity (PCP) genes Celsr1 and Vangl2 lead to disrupted lung development and defects in lung architecture. Lungs from Celsr1Crsh and Vangl2Lp mouse mutants are small and misshapen with fewer branches, and by late gestation exhibit thickened interstitial mesenchyme and defective saccular formation. We observe a recapitulation of these branching defects following inhibition of Rho kinase, an important downstream effector of the PCP signalling pathway. Moreover, epithelial integrity is disrupted, cytoskeletal remodelling perturbed and mutant endoderm does not branch normally in response to the chemoattractant FGF10. We further show that Celsr1 and Vangl2 proteins are present in restricted spatial domains within lung epithelium. Our data show that the PCP genes Celsr1 and Vangl2 are required for foetal lung development thereby revealing a novel signalling pathway critical for this process that will enhance our understanding of congenital and adult lung diseases and may in future lead to novel therapeutic strategies.

Sox9 plays multiple roles in the lung epithelium during branching morphogenesis

“…After a 30-min pulse of BrdU, we determined the percentage of proximal (Ecad+, Sox2+) and distal (Ecad+, Sox2−) proliferation in the epithelium of control and Sox9 LOF lungs at E14.5. As previously demonstrated (1,(6)(7)(8)(9)(10)(11)14), we confirmed that distal epithelial proliferation was significantly higher than proximal epithelial proliferation in control tissue (40.2% ± 1.7% vs. 29.6% ± 1.7%; P < 0.0005; n = 12) (Fig. 2B and SI Appendix, Fig.…”

“…These saccules will eventually give rise to mature alveoli in the adult mouse (2)(3)(4)(5). Several signaling pathways and transcription factors are known to play roles in branching morphogenesis; however, mechanisms controlling morphogenetic movements in the lungs have only recently started to gain attention (1,(6)(7)(8)(9)(10)(11).…”

Deficiency of the Planar Cell Polarity Protein Vangl2 in Podocytes Affects Glomerular Morphogenesis and Increases Susceptibility to Injury

“…14 The PCP pathway is known to govern various processes from collective cell migration to convergent extension and oriented cell division during vertebrate tissue morphogenesis. 15 Mouse mutations in several PCP genes (including Van Gogh-like protein 2 [Vangl2] 16 and others) cause severe congenital defects in many organs, including heart, lung, and ear; the most notable among them, a severe neural tube defect, craniorachischisis [16][17][18][19] ; these mice die in utero around E17.5-E18.5 (E, embryonic day). Mutations in Vangl2 and other PCP genes have been associated with neural tube defects in humans.…”

Replication of the CELSR1 association with ischemic stroke in a Portuguese case-control cohort

“…This unusual grouping of motifs generates a plasma membrane molecule capable of signaling after self-recognition in neighboring cell:cell interfaces or through heterophilic ligand/receptor inter- actions [9]. Celsr1 is a key component of the planar cell polarity pathway which directs the re-structuring of epithelial tissue during development of several tissues [10]. The rs4044210 SNP is located in the hormone receptor domain of Celsr1, an extracellular domain containing four conserved cysteine residues likely form disulfide bridges and which may function as a ligand-binding domain.…”