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dc.contributor.authorShaikh, Lalarukh Harisen
dc.contributor.authorZhou, Junhuaen
dc.contributor.authorTeo, Adaen
dc.contributor.authorGarg, Sumedhaen
dc.contributor.authorNeogi, Sudeshna Guhaen
dc.contributor.authorFigg, Nicholaen
dc.contributor.authorYeo, Gilesen
dc.contributor.authorYu, Haixiangen
dc.contributor.authorMaguire, Janeten
dc.contributor.authorZhao, Wanfengen
dc.contributor.authorBennett, Martinen
dc.contributor.authorAzizan, Elena ABen
dc.contributor.authorDavenport, Anthonyen
dc.contributor.authorMcKenzie, Grahameen
dc.contributor.authorBrown, Morris Jen
dc.date.accessioned2015-06-05T09:46:17Z
dc.date.available2015-06-05T09:46:17Z
dc.date.issued2015-04-27en
dc.identifier.citationShaikh et al. Journal of Clinical Endocrinology and Metabolism (2015) Vol. 100, Issue 6, pp. E836-E844 . DOI: 10.1210/jc.2015-1734en
dc.identifier.issn0021-972X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/248273
dc.description.abstractContext: Aldosterone synthesis and cellularity in the human adrenal zona glomerulosa (ZG) is sparse and patchy, presumed due to salt excess. The frequency of somatic mutations causing aldosterone-producing adenomas (APA) may be a consequence of protection from cell loss by constitutive aldosterone production. Objective: To delineate a process in human ZG which may regulate both aldosterone production and cell turnover. Design: Comparison of 20 pairs of ZG and zona fasciculata (ZF) transcriptomes from adrenals adjacent to an APA (n=13) or a pheochromocytoma (n=7). Interventions: Over-expression of top ZG gene (LGR5), or stimulation by its ligand (R-spondin-3). Main Outcome Measures: 1) Transcriptome profile of ZG and ZF; 2) Aldosterone production, cell kinetic measurements, and Wnt signaling activity of LGR5 transfected or R-spondin-3-stimulated cells. Results: LGR5 was the top gene up-regulated in ZG (25-fold). The gene for its cognate ligand R-spondin-3, RSPO3, was 5-fold up-regulated. In total, 18 genes associated with the Wnt pathway were >2-fold up-regulated. ZG selectivity of LGR5, and its absence in most APAs, were confirmed by qPCR and immunohistochemistry. Both R-spondin-3 stimulation and LGR5 transfection of human adrenal cells suppressed aldosterone production. There was reduced proliferation and increased apoptosis of transfected cells, and the non-canonical AP-1/Jun pathway was stimulated more than the canonical Wnt pathway (3-fold vs. 1.3-fold). ZG of adrenal sections stained positive for apoptosis markers. Conclusion: LGR5 is the most selectively expressed gene in human ZG, and reduces aldosterone production and cell number. Such conditions may favour cells whose somatic mutation reverses aldosterone inhibition and cell loss.
dc.description.sponsorshipThis work was supported by MJB is an NIHR Senior Investigator NF-SI-0512–10 052; LHS holds a British Heart Foundation PhD studentship FS/11/35/28871; JZ holds a Cambridge Overseas Trust Scholarship; AEDT is funded by the Wellcome Trust Translational Medicine and Therapeutics program 085 686/Z/08/A, and by Singapore A* program; EABA was supported by the Austin Doyle Award (Servier Australia); LHS, JZ and EABA were additionally supported by the NIHR Cambridge Biomedical Research Centre; GM are funded by MRC Programme Grants RDAG/287 and SKAG/001 awarded to Ashok Venkitaraman.
dc.languageEnglishen
dc.language.isoenen
dc.publisherEndocrine Society
dc.titleLGR5 activates non-canonical Wnt-signaling and inhibits aldosterone production in the human adrenal.en
dc.typeArticle
dc.description.versionThis is the author accepted manuscript. The final version is available from the Endocrine Society via http://dx.doi.org/10.1210/jc.2015-1734en
prism.endingPageE844
prism.publicationDate2015en
prism.publicationNameJournal of Clinical Endocrinology and Metabolismen
prism.startingPageE836
prism.volume100en
dc.rioxxterms.funderNIHR
dc.rioxxterms.funderBHF
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.funderMRC
dc.rioxxterms.projectidNF-SI-0512–10 052
dc.rioxxterms.projectidFS/11/35/28871
dc.rioxxterms.projectid085 686/Z/08/A
dc.rioxxterms.projectidRDAG/287
dc.rioxxterms.projectidSKAG/001
rioxxterms.versionofrecord10.1210/jc.2015-1734en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-04-27en
dc.contributor.orcidTeo, Ada [0000-0002-8832-0409]
dc.contributor.orcidYeo, Giles [0000-0001-8823-3615]
dc.contributor.orcidMaguire, Janet [0000-0002-9254-7040]
dc.contributor.orcidBennett, Martin [0000-0002-2565-1825]
dc.contributor.orcidDavenport, Anthony [0000-0002-2096-3117]
dc.identifier.eissn1945-7197
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (085686/Z/08/A)
pubs.funder-project-idBritish Heart Foundation (FS/11/35/28871)
pubs.funder-project-idBritish Heart Foundation (FS/12/33/29561)
pubs.funder-project-idBritish Heart Foundation (FS/14/12/30540)
pubs.funder-project-idBritish Heart Foundation (RG/13/14/30314)
pubs.funder-project-idBritish Heart Foundation (FS/12/8/29377)
pubs.funder-project-idMRC (MC_UU_12012/5)
pubs.funder-project-idBritish Heart Foundation (FS/14/75/31134)
pubs.funder-project-idBritish Heart Foundation (PG/07/085/23349)
pubs.funder-project-idBritish Heart Foundation (SP/08/002/24118)
pubs.funder-project-idMRC (G1000847)
pubs.funder-project-idMRC (G0800784)
pubs.funder-project-idMedical Research Council (MC_UU_12012/5/B)


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