Glucocorticoid signalling drives reduced versican levels in the fetal mouse lung

in Journal of Molecular Endocrinology

Correspondence should be addressed to T J Cole: tim.cole@monash.edu
Restricted access

Glucocorticoid (GC) signaling via the glucocorticoid receptor (GR) is essential for lung maturation in mammals. Previous studies using global or conditional mouse model knockouts of the GR gene have established that GR-mediated signaling in the interstitial mesenchyme of the fetal lung is critical for normal lung development. Screens for downstream GC-targets in conditional mesenchymal GR deficient mouse lung (GRmesKO) identified Versican (Vcan), an important extracellular matrix component and cell proliferation regulator, as a potential GR-regulated target. We show that, of the five major VCAN isoforms, the VCAN-V1 isoform containing the GAGβ domain is the predominant VCAN isoform in the fetal mouse lung distal mesenchyme at both E16.5 and E18.5, whereas the GAGα-specific VCAN-V2 isoform was only localized to the smooth muscle surrounding proximal airways. Both Vcan-V1 mRNA and protein levels were strongly overexpressed in the GRmesKO lung at E18.5. Finally, we investigated the GC regulation of the ECM protease ADAMTS 12 and showed that Adamts 12 mRNA levels were markedly reduced at E18.5 in GRmesKO fetal mouse lung and were strongly induced by both cortisol and betamethasone in cultures of primary rat fetal lung fibroblasts. ADAMTS12 protein immunoreactivity was also strongly increased in the distal lung at E18.5, after dexamethasone treatment in utero. In summary, glucocorticoid signaling via GR represses GAGβ domain-containing VCAN isoforms in distal lung mesenchyme in vivo by repressing Vcan gene expression and, in part, by inducing the ECM protease ADAMTS12, thereby contributing to the control of ECM remodelling and lung cell proliferation prior to birth.

 

      Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 201 201 77
Full Text Views 20 20 13
PDF Downloads 13 13 8
  • BirdADTanKHOlssonPFZiebaMFlecknoeSJLiddicoatDRMollardRHooperSBColeTJ 2007 Identification of glucocorticoid-regulated genes that control cell proliferation during murine respiratory development. Journal of Physiology 187201. (https://doi.org/10.1113/jphysiol.2007.136796)

    • Search Google Scholar
    • Export Citation
  • BirdADChooYLHooperSBMcDougallARColeTJ 2014 Mesenchymal glucocorticoid receptor regulates the development of multiple cell layers of the mouse lung. American Journal of Respiratory Cell and Molecular Biology 419428. (https://doi.org/10.1165/rcmb.2013-0169OC)

    • Search Google Scholar
    • Export Citation
  • BirdADMcDougallARSeowBHooperSBColeTJ 2015 Glucocorticoid regulation of lung development: lessons learned from conditional GR knockout mice. Molecular Endocrinology 158171. (https://doi.org/10.1210/me.2014-1362)

    • Search Google Scholar
    • Export Citation
  • ColeTJBlendyJAMonaghanAPKrieglsteinKSchmidWAguzziAFantuzziGHummlerEUnsickerKSchutzG 1995 Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes and Development 16081621. (https://doi.org/10.1101/gad.9.13.1608)

    • Search Google Scholar
    • Export Citation
  • ColeTJShortKLHooperSB 2019 The science of steroids. Seminars in Fetal and Neonatal Medicine 170175. (https://doi.org/10.1016/j.siny.2019.05.005)

    • Search Google Scholar
    • Export Citation
  • FaggianJFosangAJZiebaMWallaceMJHooperSB 2007 Changes in versican and chondroitin sulfate proteoglycans during structural development of the lung. American Journal of Physiology: Regulatory Integrative and Comparative Physiology R784R792. (https://doi.org/10.1152/ajpregu.00801.2006)

    • Search Google Scholar
    • Export Citation
  • HerrigesMMorriseyEE 2014 Lung development: orchestrating the generation and regeneration of a complex organ. Development 502513. (https://doi.org/10.1242/dev.098186)

    • Search Google Scholar
    • Export Citation
  • KischelPWaltregnyDDumontBTurtoiAGreffeYKirschSDe PauwECastronovoV 2010 Versican overexpression in human breast cancer lesions: known and new isoforms for stromal tumor targeting. International Journal of Cancer 640650. (https://doi.org/10.1002/ijc.24812)

    • Search Google Scholar
    • Export Citation
  • LigginsGCHowieRN 1972 A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 515525.

    • Search Google Scholar
    • Export Citation
  • McDougallARHooperSBZahraVASozoFLoCYColeTJDoranTWallaceMJ 2011 The oncogene Trop2 regulates fetal lung cell proliferation. American Journal of Physiology: Lung Cellular and Molecular Physiology L478L489. (https://doi.org/10.1152/ajplung.00063.2011)

    • Search Google Scholar
    • Export Citation
  • McDougallARHooperSBZahraVAColeTJLoCYDoranTWallaceMJ 2013 Trop2 regulates motility and lamellipodia formation in cultured fetal lung fibroblasts. American Journal of Physiology: Lung Cellular and Molecular Physiology L508L521. (https://doi.org/10.1152/ajplung.00160.2012)

    • Search Google Scholar
    • Export Citation
  • McRaeNForganLMcNeillBAddinsallAMcCullochDVan der PoelCStupkaN 2017 Glucocorticoids improve myogenic differentiation in vitro by suppressing the synthesis of versican, a transitional matrix protein overexpressed in dystrophic skeletal muscles. International Journal of Molecular Sciences E2629. (https://doi.org/10.3390/ijms18122629)

    • Search Google Scholar
    • Export Citation
  • MilevPMaurelPChibaAMevissenMPoppSYamaguchiYMargolisRKMargolisRU 1998 Differential regulation of expression of hyaluronan-binding proteoglycans in developing brain: aggrecan, versican, neurocan, and brevican. Biochemical and Biophysical Research Communications 207212. (https://doi.org/10.1006/bbrc.1998.8759)

    • Search Google Scholar
    • Export Citation
  • MooreXLHoongIColeTJ 2000 Expression of the 11beta-hydroxysteroid dehydrogenase 2 gene in the mouse. Kidney International 13071312. (https://doi.org/10.1046/j.1523-1755.2000.00967.x)

    • Search Google Scholar
    • Export Citation
  • MuramatsuT 2014 Structure and function of midkine as the basis of its pharmacological effects. British Journal of Pharmacology 814826. (https://doi.org/10.1111/bph.12353)

    • Search Google Scholar
    • Export Citation
  • NandadasaSFoulcerSApteSS 2014 The multiple, complex roles of versican and its proteolytic turnover by ADAMTS proteases during embryogenesis. Matrix Biology 3441. (https://doi.org/10.1016/j.matbio.2014.01.005)

    • Search Google Scholar
    • Export Citation
  • OshikaELiuSUngLPSinghGShinozukaHMichalopoulosGKKatyalSL 1998 Glucocorticoid-induced effects on pattern formation and epithelial cell differentiation in early embryonic rat lungs. Pediatric Research 305314. (https://doi.org/10.1203/00006450-199803000-00001)

    • Search Google Scholar
    • Export Citation
  • PaulissenGEl HourMRocksNGuedersMMBureauFFoidartJMLopez-OtinCNoelACataldoDD 2012 Control of allergen-induced inflammation and hyperresponsiveness by the metalloproteinase ADAMTS-12. Journal of Immunology 41354143. (https://doi.org/10.4049/jimmunol.1103739)

    • Search Google Scholar
    • Export Citation
  • RicciardelliCSakkoAJWeenMPRussellDLHorsfallDJ 2009 The biological role and regulation of versican levels in cancer. Cancer Metastasis Reviews 233245. (https://doi.org/10.1007/s10555-009-9182-y)

    • Search Google Scholar
    • Export Citation
  • RobertsDDalzielS 2006 Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews Cd004454. (https://doi.org/10.1002/14651858.CD004454.pub2)

    • Search Google Scholar
    • Export Citation
  • SandyJDWestlingJKenagyRDIruela-ArispeMLVerscharenCRodriguez-MazanequeJCZimmermannDRLemireJMFischerJWWightTN 2001 Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. Journal of Biological Chemistry 1337213378. (https://doi.org/10.1074/jbc.M009737200)

    • Search Google Scholar
    • Export Citation
  • SeowBKLMcDougallARAShortKLWallaceMJHooperSBColeTJ 2019 Identification of betamethasone-regulated target genes and cell pathways in fetal rat lung mesenchymal fibroblasts. Endocrinology 18681884. (https://doi.org/10.1210/en.2018-01071)

    • Search Google Scholar
    • Export Citation
  • ShengWWangGWangYLiangJWenJZhengPSWuYLeeVSlingerlandJDumontD 2005 The roles of versican V1 and V2 isoforms in cell proliferation and apoptosis. Molecular Biology of the Cell 13301340. (https://doi.org/10.1091/mbc.e04-04-0295)

    • Search Google Scholar
    • Export Citation
  • ShengWWangGLa PierreDPWenJDengZWongCKLeeDYYangBB 2006 Versican mediates mesenchymal-epithelial transition. Molecular Biology of the Cell 20092020. (https://doi.org/10.1091/mbc.e05-10-0951)

    • Search Google Scholar
    • Export Citation
  • SnyderJMWashingtonIMBirklandTChangMYFrevertCW 2015 Correlation of versican expression, accumulation, and degradation during embryonic development by quantitative immunohistochemistry. Journal of Histochemistry and Cytochemistry 952967. (https://doi.org/10.1369/0022155415610383)

    • Search Google Scholar
    • Export Citation
  • StantonHMelroseJLittleCBFosangAJ 2011 Proteoglycan degradation by the ADAMTS family of proteinases. Biochimica and Biophysica Acta 16161629. (https://doi.org/10.1016/j.bbadis.2011.08.009)

    • Search Google Scholar
    • Export Citation
  • WestlingJGottschallPEThompsonVPCockburnAPeridesGZimmermannDRSandyJD 2004 ADAMTS4 (aggrecanase-1) cleaves human brain versican V2 at Glu405-Gln406 to generate glial hyaluronate binding protein. Biochemical Journal 787795. (https://doi.org/10.1042/BJ20030896)

    • Search Google Scholar
    • Export Citation
  • WightTN 2002 Versican: a versatile extracellular matrix proteoglycan in cell biology. Current Opinion in Cell Biology 617623. (https://doi.org/10.1016/s0955-0674(02)00375-7)

    • Search Google Scholar
    • Export Citation
  • WongSBrennanFEYoungMJFullerPJColeTJ 2007 A direct effect of aldosterone on endothelin-1 gene expression in vivo. Endocrinology 15111517. (https://doi.org/10.1210/en.2006-0965)

    • Search Google Scholar
    • Export Citation
  • ZhanYPurtonJFGodfreyDIColeTJHeathWRLewAM 2003 Without peripheral interference, thymic deletion is mediated in a cohort of double-positive cells without classical activation. PNAS 11971202. (https://doi.org/10.1073/pnas.0237316100)

    • Search Google Scholar
    • Export Citation
  • ZimmermannDRRuoslahtiE 1989 Multiple domains of the large fibroblast proteoglycan, versican. EMBO Journal 29752981. (https://doi.org/10.1002/j.1460-2075.1989.tb08447.x)

    • Search Google Scholar
    • Export Citation
  • ZouKMuramatsuHIkematsuSSakumaSSalamaRHShinomuraTKimataKMuramatsuT 2000 A heparin-binding growth factor, midkine, binds to a chondroitin sulfate proteoglycan, PG-M/versican. European Journal of Biochemistry 40464053. (https://doi.org/10.1046/j.1432-1327.2000.01440.x)

    • Search Google Scholar
    • Export Citation