LGR5 activates noncanonical Wnt signaling and inhibits aldosterone production in the human adrenal

Lalarukh Haris Shaikh, Junhua Zhou, Ada E D Teo, Sumedha Garg, Sudeshna Guha Neogi, Nichola Figg, Giles S. Yeo, Haixiang Yu, Janet J. Maguire, Wanfeng Zhao, Martin R. Bennett, Azizan Elena Aisha, Anthony P. Davenport, Grahame McKenzie, Morris J. Brown

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Context: Aldosterone synthesis and cellularity in the human adrenal zona glomerulosa (ZG) is sparse and patchy, presumably due to salt excess. The frequency of somatic mutations causing aldosterone-producing adenomas (APAs) may be a consequence of protection from cell loss by constitutive aldosterone production. Objective: The objective of the study was to delineate a process in human ZG, which may regulate both aldosterone production and cell turnover. Design: This study included a comparison of 20 pairs of ZG and zona fasciculata transcriptomes from adrenals adjacent to an APA (n = 13) or a pheochromocytoma (n = 7). Interventions: Interventions included an overexpression of the top ZG gene (LGR5) or stimulation by its ligand (R-spondin-3). Main Outcome Measures: A transcriptome profile of ZG and zona fasciculata and aldosterone production, cell kinetic measurements, and Wnt signaling activity of LGR5 transfected or R-spondin-3-stimulated cells were measured. 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 greater than 2-fold up-regulated. ZG selectivity of LGR5, and its absence in most APAs, were confirmed by quantitative PCR 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 noncanonical activator protein- 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 favor cells whose somatic mutation reverses aldosterone inhibition and cell loss.

Original languageEnglish
Pages (from-to)E836-E844
JournalJournal of Clinical Endocrinology and Metabolism
Volume100
Issue number6
DOIs
Publication statusPublished - 1 Jun 2015

Fingerprint

Zona Glomerulosa
Aldosterone
Genes
Adenoma
Zona Fasciculata
Wnt Signaling Pathway
Transcriptome
Apoptosis
Ligands
Cytoprotection
Transcription Factor AP-1
Pheochromocytoma
Mutation Rate
Transfection
Salts
Cell Count
Immunohistochemistry
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Shaikh, L. H., Zhou, J., Teo, A. E. D., Garg, S., Neogi, S. G., Figg, N., ... Brown, M. J. (2015). LGR5 activates noncanonical Wnt signaling and inhibits aldosterone production in the human adrenal. Journal of Clinical Endocrinology and Metabolism, 100(6), E836-E844. https://doi.org/10.1210/jc.2015-1734

LGR5 activates noncanonical Wnt signaling and inhibits aldosterone production in the human adrenal. / Shaikh, Lalarukh Haris; Zhou, Junhua; Teo, Ada E D; Garg, Sumedha; Neogi, Sudeshna Guha; Figg, Nichola; Yeo, Giles S.; Yu, Haixiang; Maguire, Janet J.; Zhao, Wanfeng; Bennett, Martin R.; Elena Aisha, Azizan; Davenport, Anthony P.; McKenzie, Grahame; Brown, Morris J.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 100, No. 6, 01.06.2015, p. E836-E844.

Research output: Contribution to journalArticle

Shaikh, LH, Zhou, J, Teo, AED, Garg, S, Neogi, SG, Figg, N, Yeo, GS, Yu, H, Maguire, JJ, Zhao, W, Bennett, MR, Elena Aisha, A, Davenport, AP, McKenzie, G & Brown, MJ 2015, 'LGR5 activates noncanonical Wnt signaling and inhibits aldosterone production in the human adrenal', Journal of Clinical Endocrinology and Metabolism, vol. 100, no. 6, pp. E836-E844. https://doi.org/10.1210/jc.2015-1734
Shaikh, Lalarukh Haris ; Zhou, Junhua ; Teo, Ada E D ; Garg, Sumedha ; Neogi, Sudeshna Guha ; Figg, Nichola ; Yeo, Giles S. ; Yu, Haixiang ; Maguire, Janet J. ; Zhao, Wanfeng ; Bennett, Martin R. ; Elena Aisha, Azizan ; Davenport, Anthony P. ; McKenzie, Grahame ; Brown, Morris J. / LGR5 activates noncanonical Wnt signaling and inhibits aldosterone production in the human adrenal. In: Journal of Clinical Endocrinology and Metabolism. 2015 ; Vol. 100, No. 6. pp. E836-E844.
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abstract = "Context: Aldosterone synthesis and cellularity in the human adrenal zona glomerulosa (ZG) is sparse and patchy, presumably due to salt excess. The frequency of somatic mutations causing aldosterone-producing adenomas (APAs) may be a consequence of protection from cell loss by constitutive aldosterone production. Objective: The objective of the study was to delineate a process in human ZG, which may regulate both aldosterone production and cell turnover. Design: This study included a comparison of 20 pairs of ZG and zona fasciculata transcriptomes from adrenals adjacent to an APA (n = 13) or a pheochromocytoma (n = 7). Interventions: Interventions included an overexpression of the top ZG gene (LGR5) or stimulation by its ligand (R-spondin-3). Main Outcome Measures: A transcriptome profile of ZG and zona fasciculata and aldosterone production, cell kinetic measurements, and Wnt signaling activity of LGR5 transfected or R-spondin-3-stimulated cells were measured. 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 greater than 2-fold up-regulated. ZG selectivity of LGR5, and its absence in most APAs, were confirmed by quantitative PCR 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 noncanonical activator protein- 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 favor cells whose somatic mutation reverses aldosterone inhibition and cell loss.",
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AU - Zhou, Junhua

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AU - Garg, Sumedha

AU - Neogi, Sudeshna Guha

AU - Figg, Nichola

AU - Yeo, Giles S.

AU - Yu, Haixiang

AU - Maguire, Janet J.

AU - Zhao, Wanfeng

AU - Bennett, Martin R.

AU - Elena Aisha, Azizan

AU - Davenport, Anthony P.

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