Dis Model Mech. 2023 Jun 1;16(6): dmm050053. doi: 10.1242/dmm.050053
Crosstalk between androgen receptor and WNT/β-catenin signaling causes sex-specific adrenocortical hyperplasia in mice
Rodanthi Lyraki1, Anaëlle Grabek1, Amélie Tison1, Lahiru Chamara Weerasinghe Arachchige1, Mirko Peitzsch2, Nicole Bechmann2,3, Sameh A Youssef4,5, Alain de Bruin4,6, Elvira R M Bakker7, Frank Claessens8, Marie-Christine Chaboissier1, Andreas Schedl1
1Université Côte d’Azur, Inserm, CNRS, Institut de Biologie Valrose, 06108 Nice, France.
2Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
3Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
4Dutch Molecular Pathology Center, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CL, Utrecht, the Netherlands.
5Janssen Research and Development, 2340 Beerse, Belgium.
6Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, the Netherlands.
7Department of Pathology, University Medical Center Utrecht, 3508 AB, Utrecht, the Netherlands.
8Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium.
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.