Crosstalk between androgen receptor and WNT/β-catenin signaling causes sex-specific adrenocortical hyperplasia in mice

Rodanthi Lyraki; Anaëlle Grabek; Amélie Tison; Lahiru Chamara Weerasinghe Arachchige; Mirko Peitzsch; Nicole Bechmann; Sameh A. Youssef; Alain de Bruin; Elvira R.M. Bakker; Frank Claessens; Marie Christine Chaboissier; Andreas Schedl

doi:10.1242/dmm.050053

Crosstalk between androgen receptor and WNT/β-catenin signaling causes sex-specific adrenocortical hyperplasia in mice

Rodanthi Lyraki, Anaëlle Grabek, Amélie Tison, Lahiru Chamara Weerasinghe Arachchige, Mirko Peitzsch, Nicole Bechmann, Sameh A. Youssef, Alain de Bruin, Elvira R.M. Bakker, Frank Claessens, Marie Christine Chaboissier, Andreas Schedl^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Female bias is highly prevalent in conditions such as adrenal cortex hyperplasia and neoplasia, but the reasons behind this phenomenon are poorly understood. In this study, we show that overexpression of the secreted WNT agonist R-spondin 1 (RSPO1) leads to ectopic activation of WNT/β-catenin signaling and causes sex-specific adrenocortical hyperplasia in mice. Although female adrenals show ectopic proliferation, male adrenals display excessive immune system activation and cortical thinning. Using a combination of genetic manipulations and hormonal treatment, we show that gonadal androgens suppress ectopic proliferation in the adrenal cortex and determine the selective regulation of the WNT-related genes Axin2 and Wnt4. Notably, genetic removal of androgen receptor (AR) from adrenocortical cells restores the mitogenic effect of WNT/β-catenin signaling. This is the first demonstration that AR activity in the adrenal cortex determines susceptibility to canonical WNT signaling-induced hyperplasia.

Original language	English
Article number	dmm050053
Journal	DMM Disease Models and Mechanisms
Volume	16
Issue number	6
DOIs	https://doi.org/10.1242/dmm.050053
Publication status	Published - Jun 2023

Keywords

Adrenocortical hyperplasia
Androgen receptor
R-spondin signaling
Sexual dimorphism

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10.1242/dmm.050053Licence: CC BY

dmm050053Final published version, 22.6 MBLicence: CC BY

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Lyraki, R., Grabek, A., Tison, A., Arachchige, L. C. W., Peitzsch, M., Bechmann, N., Youssef, S. A., de Bruin, A., Bakker, E. R. M., Claessens, F., Chaboissier, M. C., & Schedl, A. (2023). Crosstalk between androgen receptor and WNT/β-catenin signaling causes sex-specific adrenocortical hyperplasia in mice. DMM Disease Models and Mechanisms, 16(6), Article dmm050053. https://doi.org/10.1242/dmm.050053

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title = "Crosstalk between androgen receptor and WNT/β-catenin signaling causes sex-specific adrenocortical hyperplasia in mice",

abstract = "Female bias is highly prevalent in conditions such as adrenal cortex hyperplasia and neoplasia, but the reasons behind this phenomenon are poorly understood. In this study, we show that overexpression of the secreted WNT agonist R-spondin 1 (RSPO1) leads to ectopic activation of WNT/β-catenin signaling and causes sex-specific adrenocortical hyperplasia in mice. Although female adrenals show ectopic proliferation, male adrenals display excessive immune system activation and cortical thinning. Using a combination of genetic manipulations and hormonal treatment, we show that gonadal androgens suppress ectopic proliferation in the adrenal cortex and determine the selective regulation of the WNT-related genes Axin2 and Wnt4. Notably, genetic removal of androgen receptor (AR) from adrenocortical cells restores the mitogenic effect of WNT/β-catenin signaling. This is the first demonstration that AR activity in the adrenal cortex determines susceptibility to canonical WNT signaling-induced hyperplasia.",

keywords = "Adrenocortical hyperplasia, Androgen receptor, R-spondin signaling, Sexual dimorphism",

author = "Rodanthi Lyraki and Ana{\"e}lle Grabek and Am{\'e}lie Tison and Arachchige, {Lahiru Chamara Weerasinghe} and Mirko Peitzsch and Nicole Bechmann and Youssef, {Sameh A.} and {de Bruin}, Alain and Bakker, {Elvira R.M.} and Frank Claessens and Chaboissier, {Marie Christine} and Andreas Schedl",

year = "2023",

month = jun,

doi = "10.1242/dmm.050053",

language = "English",

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Lyraki, R, Grabek, A, Tison, A, Arachchige, LCW, Peitzsch, M, Bechmann, N, Youssef, SA, de Bruin, A, Bakker, ERM, Claessens, F, Chaboissier, MC & Schedl, A 2023, 'Crosstalk between androgen receptor and WNT/β-catenin signaling causes sex-specific adrenocortical hyperplasia in mice', DMM Disease Models and Mechanisms, vol. 16, no. 6, dmm050053. https://doi.org/10.1242/dmm.050053

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AU - Lyraki, Rodanthi

AU - Grabek, Anaëlle

AU - Tison, Amélie

AU - Arachchige, Lahiru Chamara Weerasinghe

AU - Peitzsch, Mirko

AU - Bechmann, Nicole

AU - Youssef, Sameh A.

AU - de Bruin, Alain

AU - Bakker, Elvira R.M.

AU - Claessens, Frank

AU - Chaboissier, Marie Christine

AU - Schedl, Andreas

PY - 2023/6

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AB - Female bias is highly prevalent in conditions such as adrenal cortex hyperplasia and neoplasia, but the reasons behind this phenomenon are poorly understood. In this study, we show that overexpression of the secreted WNT agonist R-spondin 1 (RSPO1) leads to ectopic activation of WNT/β-catenin signaling and causes sex-specific adrenocortical hyperplasia in mice. Although female adrenals show ectopic proliferation, male adrenals display excessive immune system activation and cortical thinning. Using a combination of genetic manipulations and hormonal treatment, we show that gonadal androgens suppress ectopic proliferation in the adrenal cortex and determine the selective regulation of the WNT-related genes Axin2 and Wnt4. Notably, genetic removal of androgen receptor (AR) from adrenocortical cells restores the mitogenic effect of WNT/β-catenin signaling. This is the first demonstration that AR activity in the adrenal cortex determines susceptibility to canonical WNT signaling-induced hyperplasia.

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Crosstalk between androgen receptor and WNT/β-catenin signaling causes sex-specific adrenocortical hyperplasia in mice

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