University of Oulu

Thanushiyan Poobalasingam, Laura L. Yates, Simone A. Walker, Miguel Pereira, Nina Y. Gross, Akmol Ali, Maria Kolatsi-Joannou, Marjo-Riitta Jarvelin, Juha Pekkanen, Eugenia Papakrivopoulou, David A. Long, Mark Griffiths, Darcy Wagner, Melanie Königshoff, Matthew Hind, Cosetta Minelli, Clare M. Lloyd, Charlotte H. Dean. Disease Models & Mechanisms 2017 10: 409-423; doi: 10.1242/dmm.028175

Heterozygous Vangl2Looptail mice reveal novel roles for the planar cell polarity pathway in adult lung homeostasis and repair

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Author: Poobalasingam, Thanushiyan1; Yates, Laura L.1; Walker, Simone A.1;
Organizations: 1Inflammation Repair and Development Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK
2Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London SW3 6LR, UK
3Developmental Biology and Cancer Unit, UCL Institute of Child Health, London WC1N 1EH, UK
4Department of Epidemiology and Biostatistics, MRC–PHE Centre for Environment & Health, School of Public Health, Imperial College London, London SW7 2AZ, UK
5Center for Life Course Epidemiology, Faculty of Medicine, P.O. Box 5000, University of Oulu, Oulu FI-90014 Finland
6Biocenter Oulu, P.O. Box 5000, Aapistie 5A, University of Oulu, Oulu FI-90014, Finland
7Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, P.O. Box 20, Oulu FI-90220, Finland
8National Institute for Health and Welfare, Living Environment and Health Unit, Kuopio FI-70701, Finland
9University of Helsinki, Department of Public Health, Helsinki FI-00014, Finland
10National Institute for Health Research (NIHR) Respiratory Biomedical Research Unit at the Royal Brompton
11Comprehensive Pneumology Center, Helmholtz Center Munich, Ludwig Maximilians University Munich, Munich 81377, Germany
12National Institute for Health Research (NIHR) Respiratory Biomedical Research Unit at the Royal Brompton & Harefield NHS Foundation Trust and Imperial College, London SW3 6NP, UK
13Department of Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, London SW3 6NP, UK
14Mammalian Genetics Unit, MRC Harwell Institute, Didcot OX11 0RD, UK
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 23.7 MB)
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Language: English
Published: Company of Biologists, 2017
Publish Date: 2017-06-02


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.

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Series: Disease models & mechanisms
ISSN: 1754-8403
ISSN-E: 1754-8411
ISSN-L: 1754-8403
Volume: 10
Pages: 409 - 423
DOI: 10.1242/dmm.028175
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3121 General medicine, internal medicine and other clinical medicine
Funding: DNA extraction, sample quality controls, biobank upkeep and aliquotting was performed in the National Public Health Institute, Biomedicum Helsinki, Finland and supported financially by the Academy of Finland and Biocentrum Helsinki.
Copyright information: © 2017. The authors. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.