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Title: | Mesenchymal glucocorticoid receptor regulates the development of multiple cell layers of the mouse lung. | Authors: | Choo Y.L.;Cole T.J.;McDougall A.R.A.;Bird A.D.;Hooper S.B. | Institution: | (Bird, Choo, McDougall, Cole) Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia (Hooper, McDougall) Ritchie Centre, Monash Institute of Medical Research, Clayton, VIC, Australia (Hooper) Department of Obstetrics and Gynaecology, Monash Medical Centre, Clayton, VIC, Australia | Issue Date: | 14-Feb-2014 | Copyright year: | 2014 | Publisher: | American Thoracic Society (61 Broadway 4th Floor, New York NY 10006 - 2755, United States) | Place of publication: | United States | Publication information: | American Journal of Respiratory Cell and Molecular Biology. 50 (2) (pp 419-428), 2014. Date of Publication: February 2014. | Abstract: | Endogenous glucocorticoid (GC) hormones, signaling via the GC receptor (GR), are essential for normal lung development, and synthetic GCs are routinely used to treat respiratory disorders of very preterm babies. Germline GR knockout (GR-/-) mice show immature lung morphology and severe lung cellular hyperplasia during embryogenesis and die at birth due to respiratory failure. Two recent studies have reported contradictory results regarding the necessity for GR expression in specific lung germ layers during respiratory maturation. We further investigate in detail the lung phenotype in mice with a conditional deletion of GR in the endothelium, mesenchyme, and lung epithelium. We show that loss of GR in the mesenchyme alone produces a retarded lung phenotype almost identical to that of germline GR-/- mice, including severe postnatal lethality and lung cell hyperplasia. Loss of GR in lung epithelial cells and the endothelium had no gross effect on survival or lung morphology, but loss of epithelial GR caused increased cell proliferation in multiple compartments. Mesenchymal GR loss also produced increased epithelial cell proliferation, implying the existence of GC-regulated germ layer cross-talk. Protein levels of GR-mediated cell cycle regulators, including the cyclin-dependent kinase inhibitor p21CIP1 and the growth factor midkine, were unaffected by mesenchymal GR deletion, yet expression of the extracellular matrix proteoglycan versican was up-regulated in the distal lung on loss of mesenchymal GR. These results show that GRmediated signaling from the mesenchyme regulates respiratory maturation and ultimately survival at birth and that a key GRrepressed transcriptional target in lung mesenchymal cells is versican. Copyright © 2014 by the American Thoracic Society. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1165/rcmb.2013-0169OC | Link to associated publication: | Click here for full text options | PubMed URL: | 24053134 [http://www.ncbi.nlm.nih.gov/pubmed/?term=24053134] | ISSN: | 1044-1549 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/42049 | Type: | Article | Subjects: | intracellular signaling respiratory epithelium animal cell animal experiment article bronchus muscle cell hyperplasia cell labeling cell proliferation cell survival controlled study extracellular matrix fetus lung fetus lung maturation histology immunohistochemistry *lung alveolus epithelium lung blood vessel *lung development lung endothelium lung structure *mesenchyme cell mouse nonhuman protein expression smooth muscle fiber CD31 antigen/ec [Endogenous Compound] complementary DNA/ec [Endogenous Compound] cre recombinase/ec [Endogenous Compound] cyclin dependent kinase inhibitor/ec [Endogenous Compound] cyclin dependent kinase inhibitor 1A/ec [Endogenous Compound] elastin/ec [Endogenous Compound] *glucocorticoid receptor/ec [Endogenous Compound] midkine/ec [Endogenous Compound] protein p21/ec [Endogenous Compound] versican/ec [Endogenous Compound] controlled study extracellular matrix fetus lung fetus lung maturation histology immunohistochemistry intracellular signaling lung blood vessel *lung development lung endothelium lung structure *mesenchyme cell mouse nonhuman protein expression respiratory epithelium smooth muscle fiber *lung alveolus epithelium animal cell animal experiment article bronchus muscle cell hyperplasia cell labeling cell proliferation cell survival |
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