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Title: Investigating the role of Vangl2 in the postnatal lung
Author: Poobalasingam, Thanushiyan
ISNI:       0000 0004 6423 5263
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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The non-canonical planar cell polarity (PCP) pathway is important for embryonic development of many organs including the lungs. However, comparatively little is known about the role of this pathway in adults, partly because homozygous mutations of many PCP genes result in neonatal lethality, preventing post-natal investigations. We studied Looptail (Lp) mice, which carry a dominant negative mutation in Van Gogh-like 2 (Vangl2), a core component of the PCP pathway. Importantly, heterozygous Vangl2Lp mice are viable postnatally, allowing us to study the adult lung. To investigate the role of Vangl2 in adult lungs, we used a combination of Vangl2Lp mice alongside human in vitro studies. We show that a single mutant copy of Vangl2Lp is sufficient to perturb lung development, resulting in severe airspace enlargement and decreased adult lung function. Lungs of adult Vangl2Lp/+ mice exhibit phenotypes associated with tissue damage, such as abnormal elastin organisation, elevated levels of the elastin-cleaving enzyme Mmp-12, increased MMP 9 activity, and an altered macrophage population. Furthermore, disruption of PCP signalling in embryonic Vangl2Lp lungs perturbed actin cytoskeleton organisation, and regulation of the actin interacting protein Cofilin. Directed cell migration after scratch injury was also impaired following in vitro VANGL2 knockdown. Moreover, activation of PCP signalling by Wnt5a promoted wound healing in vitro, thereby, indicating that PCP signalling can enhance cell migration in repair. In this study, we identified a novel role for PCP signalling in the adult lung. Vangl2Lp mutations perturb adult lung structure and function, and we propose that these defects are due to actin cytoskeleton driven cell migration and repair deficiencies. Moreover, our data indicates that manipulation of the PCP pathway may promote lung repair in injury and disease to provide a curative treatment for chronic lung diseases.
Supervisor: Dean, Charlotte Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral