Publications
64 results found
Dean CH, Lloyd CM, 2017, Lung Alveolar Repair: Not All Cells Are Equal, TRENDS IN MOLECULAR MEDICINE, Vol: 23, Pages: 871-873, ISSN: 1471-4914
The lungs are capable of repair but the extent to which this occurs varies widely. Recent data indicate that, following injury, different progenitor cell populations can arise, depending on the molecular environment. In turn, these result in either normal or aberrant alveolar repair. Thus, a key question in lung regenerative medicine is how to maintain a ‘Goldilocks zone’ of repair.
Crompton M, Purnell T, Tyrer HE, et al., 2017, A mutation in Nischarin causes otitis media via LIMK1 and NF-kappa B pathways, PLoS Genetics, Vol: 13, ISSN: 1553-7390
Otitis media (OM), inflammation of the middle ear (ME), is a common cause of conductive hearing impairment. Despite the importance of the disease, the aetiology of chronic and recurrent forms of middle ear inflammatory disease remains poorly understood. Studies of the human population suggest that there is a significant genetic component predisposing to the development of chronic OM, although the underlying genes are largely unknown. Using N-ethyl-N-nitrosourea mutagenesis we identified a recessive mouse mutant, edison, that spontaneously develops a conductive hearing loss due to chronic OM. The causal mutation was identified as a missense change, L972P, in the Nischarin (NISCH) gene. edison mice develop a serous or granulocytic effusion, increasingly macrophage and neutrophil rich with age, along with a thickened, inflamed mucoperiosteum. We also identified a second hypomorphic allele, V33A, with only modest increases in auditory thresholds and reduced incidence of OM. NISCH interacts with several proteins, including ITGA5 that is thought to have a role in modulating VEGF-induced angiogenesis and vascularization. We identified a significant genetic interaction between Nisch and Itga5; mice heterozygous for Itga5-null and homozygous for edison mutations display a significantly increased penetrance and severity of chronic OM. In order to understand the pathological mechanisms underlying the OM phenotype, we studied interacting partners to NISCH along with downstream signalling molecules in the middle ear epithelia of edison mouse. Our analysis implicates PAK1 and RAC1, and downstream signalling in LIMK1 and NF-κB pathways in the development of chronic OM.
Oozeer F, Yates LL, Dean C, et al., 2017, A role for core planar polarity proteins in cell contact-mediated orientation of planar cell division across the mammalian embryonic skin, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
The question of how cell division orientation is determined is fundamentally important for understanding tissue and organ shape in both healthy or disease conditions. Here we provide evidence for cell contact-dependent orientation of planar cell division in the mammalian embryonic skin. We propose a model where the core planar polarity proteins Celsr1 and Frizzled-6 (Fz6) communicate the long axis orientation of interphase basal cells to neighbouring basal mitoses so that they align their horizontal division plane along the same axis. The underlying mechanism requires a direct, cell surface, planar polarised cue, which we posit depends upon variant post-translational forms of Celsr1 protein coupled to Fz6. Our hypothesis has parallels with contact-mediated division orientation in early C. elegans embryos suggesting functional conservation between the adhesion-GPCRs Celsr1 and Latrophilin-1. We propose that linking planar cell division plane with interphase neighbour long axis geometry reinforces axial bias in skin spreading around the mouse embryo body.
Poobalasingam T, Yates LL, Walker SA, et al., 2017, Heterozygous Vangl2 looptail mice reveal novel roles for the planar cell polarity pathway in adult lung homeostasis and repair, Disease Models & Mechanisms, Vol: 10, Pages: 409-423, ISSN: 1754-8403
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 (SC
Ng-Blichfeldt JP, Alçada J, Montero MA, et al., 2017, Deficient retinoid-driven angiogenesis may contribute to failure of adult human lung regeneration in emphysema, Thorax, Vol: 72, Pages: 510-521, ISSN: 0040-6376
BACKGROUND: Molecular pathways that regulate alveolar development and adult repair represent potential therapeutic targets for emphysema. Signalling via retinoic acid (RA), derived from vitamin A, is required for mammalian alveologenesis, and exogenous RA can induce alveolar regeneration in rodents. Little is known about RA signalling in the human lung and its potential role in lung disease. OBJECTIVES: To examine regulation of human alveolar epithelial and endothelial repair by RA, and characterise RA signalling in human emphysema. METHODS: The role of RA signalling in alveolar epithelial repair was investigated with a scratch assay using an alveolar cell line (A549) and primary human alveolar type 2 (AT2) cells from resected lung, and the role in angiogenesis using a tube formation assay with human lung microvascular endothelial cells (HLMVEC). Localisation of RA synthetic (RALDH-1) and degrading (cytochrome P450 subfamily 26 A1 (CYP26A1)) enzymes in human lung was determined by immunofluorescence. Regulation of RA pathway components was investigated in emphysematous and control human lung tissue by quantitative real-time PCR and Western analysis. RESULTS: RA stimulated HLMVEC angiogenesis in vitro; this was partially reproduced with a RAR-α agonist. RA induced mRNA expression of vascular endothelial growth factor A (VEGFA) and VEGFR2. RA did not modulate AT2 repair. CYP26A1 protein was identified in human lung microvasculature, whereas RALDH-1 partially co-localised with vimentin-positive fibroblasts. CYP26A1 mRNA and protein were increased in emphysema. CONCLUSIONS: RA regulates lung microvascular angiogenesis; the endothelium produces CYP26A1 which is increased in emphysema, possibly leading to reduced RA availability. These data highlight a role for RA in maintenance of the human pulmonary microvascular endothelium.
Poobalasingam T, Salman D, Li H, et al., 2016, Imaging the lung: the old ways and the new, Histology and Histopathology, Vol: 32, Pages: 325-337, ISSN: 1699-5848
Our understanding of lung biology can be greatly enhanced by studying embryonic and postnatal lung development, and the perturbations which occur during disease. Imaging techniques provide a unique insight into these processes. A wide variety of imaging techniques have been used to study the lungs at various stages of development and disease, ranging from histological stains to more novel techniques such as single plane illumination microscopy (SPIM), intravital microscopy (IVM), and micro-computed tomography (micro-CT). Each of these tools can be used to elicit different information about the lungs and each has its own unique advantages and disadvantages for pulmonary research. In this review we assess some of the most commonly-used and novel imaging techniques available for lung research today.
Löser S, Gregory LG, Zhang Y, et al., 2016, Pulmonary ORMDL3 is critical for induction of Alternaria induced allergic airways disease, Journal of Allergy and Clinical Immunology, Vol: 139, Pages: 1496-1507.e3, ISSN: 1097-6825
BACKGROUND: Genome-wide association studies have identified the ORMDL3 (ORM (yeast)-like protein isoform 3) gene locus on human chromosome 17q to be a highly significant risk factor for childhood-onset asthma. OBJECTIVE: We sought to investigate in vivo the functional role of ORMDL3 in disease inception. METHODS: An Ormdl3 deficient mouse was generated and the role of ORMDL3 in the generation of allergic airways disease to the fungal aeroallergen Alternaria alternata determined. An adeno-associated viral vector was also utilized to reconstitute ORMDL3 expression in airway epithelial cells of Ormdl3 KO mice. RESULTS: Ormdl3 knock-out mice were found to be protected from developing allergic airways disease and showed a marked decrease in pathophysiology, including lung function and airway eosinophilia induced by Alternaria. Alternaria is a potent inducer of cellular stress and the unfolded protein response and ORMDL3 was found to play a critical role in driving the ATF6 mediated arm of this response through Xbp1 and downstream activation of the endoplasmic reticulum-associated degradation pathway. Additionally ORMDL3 mediated uric acid release, another marker of cellular stress. In the knockout mice, reconstitution of Ormdl3 transcript levels specifically in the bronchial epithelium resulted in reinstatement of susceptibility to fungal allergen-induced allergic airways disease. CONCLUSIONS: This study demonstrates that ORMDL3, an asthma susceptibility gene identified by genome-wide association studies, contributes to key pathways that promote changes in airway physiology during allergic immune responses.
Zhang Y, Dean C, Loeser S, et al., 2016, Systematic dissection of ORMDL3 function in vitro and in vivo, ERS International Congress 2016, Publisher: European Respiratory Society, ISSN: 0903-1936
ORMDL3 on human chromosome 17q21 is a major genetic influence for childhood asthma, severe asthma and asthma exacerbations. To understand further the functional roles of ORMDL3, we established both human airway epithelial models and a recombineering-generated murine Ormdl3 knockout model. The influences of ORMDL3 on inflammatory responses in vitro and in vivo were investigated.We performed gene silencing using siRNA for two days in airway epithelium cells (A549, Beas2B and NHBE cells) after which cells were stimulated with IL1B. ORMDL3 knockdown-epithelial cells released much less IL6 and IL8 at 10 hours after stimulation (P < 0.01 respectively). Over-expression of ORMDL3 in epithelial cells resulted in a significant increase in release of IL6 and IL8 shortly after stimulation. Serine-palmitoyl transferase (SPT) is the key enzyme of sphingolipid metabolism. Treatment of epithelial cells with the SPT inhibitor myriocin resulted in an increase in release of IL6 and IL8 after stimulation, mirroring the results seen with the overexpression model. A systemic metabolic screening of the ORMDL3 knockdown epithelial cells revealed ORMDL3 to be involved not only in regulating sphingolipid metabolism but also lysophospholipids metabolism and the regulation of glycolysis. Parallel global gene expression profiling of the same cells identified key transcripts involved in regulating the inflammatory response. The lung function of Ormdl3 knockout mice also exhibited a reduced response after Alternaria alternata challenge.Our findings indicate ORMDL3 is a key molecule involved in the regulation of the inflammation response through multiple pathways and is a potential therapeutic target for asthma.
Salman D, Dean C, Griffiths MJD, 2016, Cyclic Strain of Precision Cut Lung Slices (PCLS) Induces Pro-Inflammatory and Pro-Proliferative Signalling, 60th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 96A-96A, ISSN: 0006-3495
Minelli C, Dean CH, Hind M, et al., 2016, Association of Forced Vital Capacity with the Developmental Gene NCOR2, PLOS One, Vol: 11, ISSN: 1932-6203
BackgroundForced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absenceof chronic respiratory conditions. Epidemiological evidence highlights the role of early lifefactors on adult FVC, pointing to environmental exposures and genes affecting lung developmentas risk factors for low FVC later in life. Although highly heritable, a small number ofgenes have been found associated with FVC, and we aimed at identifying further geneticvariants by focusing on lung development genes.PLOS ONE | DOI:10.1371/journal.pone.0147388 February 2, 2016 1 / 17OPEN ACCESSCitation: Minelli C, Dean CH, Hind M, Alves AC,Amaral AFS, Siroux V, et al. (2016) Association ofForced Vital Capacity with the Developmental GeneNCOR2. PLoS ONE 11(2): e0147388. doi:10.1371/journal.pone.0147388Editor: Philipp Latzin, University Children's HospitalBasel, SWITZERLANDReceived: August 28, 2015Accepted: January 4, 2016Published: February 2, 2016Copyright: © 2016 Minelli et al. This is an openaccess article distributed under the terms of theCreative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in anymedium, provided the original author and source arecredited.Data Availability Statement: All relevant data arewithin the paper and its Supporting Information files.Funding: The authors have no support or funding toreport.Competing Interests: The authors have declaredthat no competing interests exist.MethodsPer-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP forthe top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and5,062 children (ALSPAC). Associations were considered replicated if the replication p-valuesurvived Bonferroni correction (p<0.002; 0.05/25), with a nominal p-value considered assuggestive evidence. For SNPs with evidence of replication, effects on the expression levelsof n
Tateossian H, Morse S, Simon MM, et al., 2015, Interactions between the otitis media gene, Fbxo11, and p53 in the mouse embryonic lung, Disease Models & Mechanisms, Vol: 8, Pages: 1531-1542, ISSN: 1754-8411
Otitis media with effusion (OME) is the most common cause of hearing loss in children, and tympanostomy (ear tube insertion) to alleviate the condition remains the commonest surgical intervention in children in the developed world. Chronic and recurrent forms of otitis media (OM) are known to have a very substantial genetic component; however, until recently, little was known of the underlying genes involved. The Jeff mouse mutant carries a mutation in the Fbxo11 gene, a member of the F-box family, and develops deafness due to a chronic proliferative OM. We previously reported that Fbxo11 is involved in the regulation of transforming growth factor beta (TGF-β) signalling by regulating the levels of phospho-Smad2 in the epithelial cells of palatal shelves, eyelids and airways of the lungs. It has been proposed that FBXO11 regulates the cell's response to TGF-β through the ubiquitination of CDT2. Additional substrates for FBXO11 have been identified, including p53. Here, we have studied both the genetic and biochemical interactions between FBXO11 and p53 in order to better understand the function of FBXO11 in epithelial development and its potential role in OM. In mice, we show that p53 (also known as Tp53) homozygous mutants and double heterozygous mutants (Jf/+ p53/+) exhibit similar epithelial developmental defects to Fbxo11 homozygotes. FBXO11 and p53 interact in the embryonic lung, and mutation in Fbxo11 prevents the interaction with p53. Both p53 and double mutants show raised levels of pSMAD2, recapitulating that seen in Fbxo11 homozygotes. Overall, our results support the conclusion that FBXO11 regulates the TGF-β pathway in the embryonic lung via cross-talk with p53.
Probert K, Lee J, Reining S, et al., 2015, Deletion Of Lung Function Associated Gene Gstcd Does Not Result In Gross Phenotypic Changes In Mice, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Alcada J, Ng-Blichfeldt JP, Proudfoot AG, et al., 2014, A NOVEL HUMAN MODEL TO STUDY ALVEOLAR INJURY AND REPAIR, Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A53-A53, ISSN: 0040-6376
Loeser S, Zhang Y, Gregory L, et al., 2014, Novel insights into the <i>in vivo</i> function of <i>Ormdl3</i> - a gene associated with the onset of childhood asthma, IMMUNOLOGY, Vol: 143, Pages: 59-59, ISSN: 0019-2805
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- Citations: 3
Ramsbottom SA, Sharma V, Rhee HJ, et al., 2014, Vangl2-Regulated Polarisation of Second Heart Field-Derived Cells Is Required for Outflow Tract Lengthening during Cardiac Development, PLOS GENETICS, Vol: 10, ISSN: 1553-7390
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- Citations: 54
Zhang Y, Dean C, Chessum L, et al., 2014, Functional analysis of a novel ENU-induced PHD finger 11 (<i>Phf11)</i> mouse mutant, MAMMALIAN GENOME, Vol: 25, Pages: 573-582, ISSN: 0938-8990
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- Citations: 2
Goggolidou P, Hadjirin NF, Bak A, et al., 2014, Atmin mediates kidney morphogenesis by modulating Wnt signaling, HUMAN MOLECULAR GENETICS, Vol: 23, Pages: 5303-5316, ISSN: 0964-6906
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- Citations: 10
Dean CH, 2014, NORMAL AND ABNORMAL LUNG DEVELOPMENT-RECENT ADVANCES, PEDIATRIC PULMONOLOGY, Vol: 49, Pages: S25-S26, ISSN: 8755-6863
Papakrivopoulou E, Dean CH, Copp AJ, et al., 2013, Planar cell polarity and the kidney, Nephrology Dialysis Transplantation, Vol: 29, Pages: 1320-1326, ISSN: 1460-2385
Dean C, Bingle C, Hind M, 2013, Delivering and phenotyping mouse models for the respiratory community: a report on the Biochemical Society Workshop, CLINICAL SCIENCE, Vol: 125, Pages: 495-500, ISSN: 0143-5221
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- Citations: 1
Yates LL, Schnatwinkel C, Hazelwood L, et al., 2013, Scribble is required for normal epithelial cell-cell contacts and lumen morphogenesis in the mammalian lung, DEVELOPMENTAL BIOLOGY, Vol: 373, Pages: 267-280, ISSN: 0012-1606
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- Citations: 59
Hasan NA, Hind M, Dean CH, 2012, MECHANISMS OF LUNG REPAIR POST INJURY: THE ROLE FOR NON-CANONICAL WNT SIGNALLING AND PLANAR CELL POLARITY, Winter Meeting of the British-Thoracic-Society 2012, Publisher: BMJ PUBLISHING GROUP, Pages: A36-A36, ISSN: 0040-6376
Thoby-Brisson M, Bouvier J, Glasco DM, et al., 2012, Brainstem respiratory oscillators develop independently of neuronal migration defects in the Wnt/PCP mouse mutant looptail, PLoS One, Vol: 7, Pages: 1-12, ISSN: 1932-6203
The proper development and maturation of neuronal circuits require precise migration of component neurons from their birthplace (germinal zone) to their final positions. Little is known about the effects of aberrant neuronal position on the functioning of organized neuronal groups, especially in mammals. Here, we investigated the formation and properties of brainstem respiratory neurons in looptail (Lp) mutant mice in which facial motor neurons closely apposed to some respiratory neurons fail to migrate due to loss of function of the Wnt/Planar Cell Polarity (PCP) protein Vangl2. Using calcium imaging and immunostaining on embryonic hindbrain preparations, we found that respiratory neurons constituting the embryonic parafacial oscillator (e-pF) settled at the ventral surface of the medulla in Vangl2Lp/+ and Vangl2Lp/Lp embryos despite the failure of tangential migration of its normally adjacent facial motor nucleus. Anatomically, the e-pF neurons were displaced medially in Lp/+ embryos and rostro-medially Lp/Lp embryos. Pharmacological treatments showed that the e-pF oscillator exhibited characteristic network properties in both Lp/+ and Lp/Lp embryos. Furthermore, using hindbrain slices, we found that the other respiratory oscillator, the preBötzinger complex, was also anatomically and functionally established in Lp mutants. Importantly, the displaced e-pF oscillator established functional connections with the preBötC oscillator in Lp/+ mutants. Our data highlight the robustness of the developmental processes that assemble the neuronal networks mediating an essential physiological function.
Yates LL, Dean CH, 2011, Planar polarity: A new player in both lung development and disease., Organogenesis, Vol: 7, Pages: 209-216, ISSN: 1547-6278
The clinical burden of both adult and neonatal lung disease worldwide is substantial; in the UK alone, respiratory disease kills one in four people. It is increasingly recognized that genes and pathways that regulate lung development, may be aberrantly activated in disease and/or reactivated as part of the lungs' intrinsic repair mechanisms. Investigating the genes and signaling pathways that regulate lung growth has led to significant insights into the pathogenesis of congenital and adult lung disease. Recently, the planar cell polarity (PCP) pathway has been shown to be required for normal lung development, and data suggests that this signaling pathway is also involved in the pathogenesis of some lung diseases. In this review, we summarize current evidence indicating that the PCP pathway is required for both lung development and disease.
Yates LL, Papakrivopoulou J, Long DA, et al., 2010, The planar cell polarity gene <i>Vangl2</i> is required for mammalian kidney-branching morphogenesis and glomerular maturation, HUMAN MOLECULAR GENETICS, Vol: 19, Pages: 4663-4676, ISSN: 0964-6906
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- Citations: 90
Paudyal A, Damrau C, Patterson VL, et al., 2010, The novel mouse mutant, chuzhoi, has disruption of Ptk7 protein and exhibits defects in neural tube, heart and lung development and abnormal planar cell polarity in the ear, BMC Developmental Biology, Vol: 10, ISSN: 1471-213X
Yates LL, Schnatwinkel C, Murdoch JN, et al., 2010, The PCP genes <i>Celsr1</i> and <i>Vangl2</i> are required for normal lung branching morphogenesis, HUMAN MOLECULAR GENETICS, Vol: 19, Pages: 2251-2267, ISSN: 0964-6906
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- Citations: 118
Yates L, McMurray F, Zhang Y, et al., 2009, ENU mutagenesis as a tool for understanding lung development and disease Biochemical Society Transactions 37: 838–842.
Warr N, Siggers P, Bogani D, et al., 2009, <i>Sfrp1</i> and <i>Sfrp2</i> are required for normal male sexual development in mice, DEVELOPMENTAL BIOLOGY, Vol: 326, Pages: 273-284, ISSN: 0012-1606
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- Citations: 72
Dean CH, Miller LAD, Smith AN, et al., 2005, Canonical Wnt signaling negatively regulates branching morphogenesis of the lung and lacrimal gland, DEVELOPMENTAL BIOLOGY, Vol: 286, Pages: 270-286, ISSN: 0012-1606
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- Citations: 80
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