IRUS Total

Heterozygous Vangl2 looptail mice reveal novel roles for the planar cell polarity pathway in adult lung homeostasis and repair

File Description SizeFormat 
409.full.pdfPublished version25.5 MBAdobe PDFView/Open
Title: Heterozygous Vangl2 looptail mice reveal novel roles for the planar cell polarity pathway in adult lung homeostasis and repair
Authors: Poobalasingam, T
Yates, LL
Walker, SA
Pereira, M
Gross, NY
Ali, A
Kolatsi-Joannou, M
Jarvelin, MR
Pekkanen, J
Papakrivopoulou, E
Long, DA
Griffiths, M
Wagner, D
Konigshoff, M
Hind, M
Minelli, C
Lloyd, CM
Dean, C
Item Type: Journal Article
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 due to the perinatal lethality of many PCP mouse mutant lines. Here we have investigated 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 the lung disease, emphysema. In vitro, VANGL2 disruption 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 (a tissue damaging insult) on lung function. Finally, we show that that PCP genes VANGL2 and SCRIBBLE (SCRIB) are significantly downregulated in lung tissue from patients with emphysema. Our data reveals an important novel role for the PCP pathway in adult lung homeostasis and repair and sheds new light on the genetic factors which may modify destructive lung diseases such as emphysema.
Issue Date: 24-Feb-2017
Date of Acceptance: 16-Feb-2017
URI: http://hdl.handle.net/10044/1/44784
DOI: https://dx.doi.org/10.1242/dmm.028175
ISSN: 1754-8403
Publisher: Company of Biologists
Start Page: 409
End Page: 423
Journal / Book Title: Disease Models & Mechanisms
Volume: 10
Copyright Statement: © 2017. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
Planar cell polarity
Lung disease
Lung homeostasis
Tissue repair
Developmental Biology
06 Biological Sciences
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:National Heart and Lung Institute