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雄激素受体与 WNT/β-连环蛋白信号转导的串扰导致雌雄小鼠肾上腺皮质增生的性别特异性。

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

机构信息

Université Côte d'Azur, Inserm, CNRS, Institut de Biologie Valrose, 06108 Nice, France.

Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.

出版信息

Dis Model Mech. 2023 Jun 1;16(6). doi: 10.1242/dmm.050053. Epub 2023 May 10.

DOI:10.1242/dmm.050053
PMID:37102205
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10184674/
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.

摘要

女性偏倚在肾上腺皮质增生和肿瘤等疾病中极为常见，但这一现象背后的原因尚不清楚。在这项研究中，我们表明，分泌型 WNT 激动剂 R-spondin 1（RSPO1）的过表达导致 WNT/β-catenin 信号的异位激活，并导致小鼠出现性别特异性肾上腺皮质增生。虽然女性肾上腺表现出异位增殖，但男性肾上腺显示出过度的免疫系统激活和皮质变薄。通过遗传操作和激素治疗的组合，我们表明性腺雄激素抑制肾上腺皮质的异位增殖，并决定了 WNT 相关基因 Axin2 和 Wnt4 的选择性调节。值得注意的是，从肾上腺皮质细胞中去除雄激素受体（AR）会恢复 WNT/β-catenin 信号的促有丝分裂作用。这是首次证明肾上腺皮质中的 AR 活性决定了对经典 WNT 信号诱导的增生的易感性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecee/10184674/42f981c5fc36/dmm-16-050053-g6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecee/10184674/526317243b25/dmm-16-050053-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecee/10184674/24c782b4ceac/dmm-16-050053-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecee/10184674/19e99ffde317/dmm-16-050053-g3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecee/10184674/1fff44a0c342/dmm-16-050053-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecee/10184674/6bb04f92aa78/dmm-16-050053-g5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecee/10184674/42f981c5fc36/dmm-16-050053-g6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecee/10184674/526317243b25/dmm-16-050053-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecee/10184674/24c782b4ceac/dmm-16-050053-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecee/10184674/19e99ffde317/dmm-16-050053-g3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecee/10184674/1fff44a0c342/dmm-16-050053-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecee/10184674/6bb04f92aa78/dmm-16-050053-g5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecee/10184674/42f981c5fc36/dmm-16-050053-g6.jpg

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