title: HeterozygousVangl2Looptailmice 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 heterozygousLooptail(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 thatVangl2Lp/+lungs exhibit altered distribution of actin microfilaments and abnormal regulation of the actin-modifying protein cofilin. In addition, we show thatVangl2Lp/+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 ofVANGL2impairs 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 betweenVANGL2and smoking on lung function. Finally, we show that PCP genesVANGL2andSCRIBare 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.
authors.affiliation: Inflammation Repair and Development Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Thanushiyan
authors.initials: T
authors.lastname: Poobalasingam
authors.affiliation: Inflammation Repair and Development Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Yates
authors.affiliation: Inflammation Repair and Development Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Simone A
authors.initials: SA
authors.lastname: Walker
authors.affiliation: Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London SW3 6LR, UK.
authors.forename: Miguel
authors.initials: M
authors.lastname: Pereira
authors.affiliation: Inflammation Repair and Development Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Nina Y
authors.initials: NY
authors.lastname: Gross
authors.affiliation: Inflammation Repair and Development Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Akmol
authors.initials: A
authors.lastname: Ali
authors.affiliation: Developmental Biology and Cancer Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Kolatsi-Joannou
authors.affiliation: Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London SW7 2AZ, UK.|Center for Life Course Epidemiology, Faculty of Medicine, P.O. Box 5000, University of Oulu, Oulu FI-90014 Finland.|Biocenter Oulu, P.O. Box 5000, Aapistie 5A, University of Oulu, Oulu FI-90014, Finland.|Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, P.O. Box 20, Oulu FI-90220, Finland.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Jarvelin
authors.affiliation: National Institute for Health and Welfare, Living Environment and Health Unit, Kuopio FI-70701, Finland.|University of Helsinki, Department of Public Health, Helsinki FI-00014, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Pekkanen
authors.affiliation: Developmental Biology and Cancer Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Papakrivopoulou
authors.affiliation: Developmental Biology and Cancer Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Long
authors.affiliation: Inflammation Repair and Development Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.|National Institute for Health Research (NIHR) Respiratory Biomedical Research Unit at the Royal Brompton & Harefield NHS Foundation Trust and Imperial College, London SW3 6NP, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Griffiths
authors.affiliation: Comprehensive Pneumology Center, Helmholtz Center Munich, Ludwig Maximilians University Munich, Munich 81377, Germany.
authors.forename: Darcy
authors.initials: D
authors.lastname: Wagner
authors.affiliation: Comprehensive Pneumology Center, Helmholtz Center Munich, Ludwig Maximilians University Munich, Munich 81377, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Königshoff
authors.affiliation: Inflammation Repair and Development Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.|National Institute for Health Research (NIHR) Respiratory Biomedical Research Unit at the Royal Brompton & Harefield NHS Foundation Trust and Imperial College, London SW3 6NP, UK.|Department of Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, London SW3 6NP, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hind
authors.affiliation: Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London SW3 6LR, UK.
authors.forename: Cosetta
authors.initials: C
authors.lastname: Minelli
authors.affiliation: Inflammation Repair and Development Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Clare M
authors.initials: CM
authors.lastname: Lloyd
authors.affiliation: Inflammation Repair and Development Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK c.dean@imperial.ac.uk.|Mammalian Genetics Unit, MRC Harwell Institute, Didcot OX11 0RD, UK.
authors.forename: Charlotte H
authors.identifier: 0000-0002-8846-5472
authors.initials: CH
authors.lastname: Dean
mesh_terms: D000072283:A549 Cells; D008841:Actin Cytoskeleton / Q000378:metabolism; D000375:Aging / Q000473:pathology*; D000818:Animals; D002465:Cell Movement; D016764:Cell Polarity; D015536:Down-Regulation / Q000235:genetics; D004549:Elastin / Q000378:metabolism; D004622:Embryo, Mammalian / Q000473:pathology; D055785:Gene Knockdown Techniques; D006579:Heterozygote; D006706:Homeostasis; D006801:Humans; D008168:Lung / Q000196:embryology / Q000473:pathology* / Q000503:physiopathology; D008264:Macrophages / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics; D012907:Smoking / Q000009:adverse effects; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing
chemical_list: C431577:Ltap protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C480591:SCRIB protein, human; D025521:Tumor Suppressor Proteins; D004549:Elastin
keywords: Cytoskeleton; Lung disease; Lung homeostasis; Planar cell polarity; Tissue repair; Vangl2