Progesterone initiates Wnt-β-catenin signaling but estradiol is required for nuclear activation and synchronous proliferation of rat uterine stromal cells

Virginia Rider, Kazuto ISUZUGAWA, Meryl Twarog, Stacy Jones, Brent D. Cameron, Kazuhiko Imakawa, Jianwen Fang
In: Journal of Endocrinology · 2006 · vol. 191(3) , pp. 537–548 · doi:10.1677/joe.1.07030 · PMID:17170212 · W2121946977
article OA: bronze CC0 ⤵ 4 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

Progesterone primes rat uterine stromal cells for estradiol-induced synchronous proliferation by initiating Wnt signaling via GSK-3beta downregulation, but estradiol is required for beta-catenin nuclear activation and Wnt target gene expression.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-09 ⓘ

Using ovariectomized adult rats, the study examined how sequential progesterone and estradiol regulate Wnt/β-catenin signaling in uterine stromal cells, assessing hormone-driven changes in Wnt pathway effectors and targets by microarray and protein localization by immunohistochemistry and western blotting. Progesterone pretreatment decreased GSK-3β expression in uterine stroma and was associated with β-catenin accumulation in stromal cells, while estradiol was required for β-catenin nuclear translocation and increased β-catenin/TCF-LEF binding to support synchronized stromal cell cycle entry; progesterone also increased the Wnt target uPA-R expression, which rose further with estradiol. The main limitation is that the findings are based on an ovariectomized rat hormone regimen and uterine stromal tissue/cell models, which may not fully capture human reproductive-pathology contexts. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Progesterone pretreatment of ovariectomized rat uteri increases the number of synchronously proliferating stromal cells in response to estradiol 17-beta. To identify the signals involved in stimulating synchronous proliferation, sexually mature ovariectomized rats were injected with progesterone (2 mg) for 3 consecutive days. Estradiol 17-beta (0.2 microg) was administered to initiate cell cycle entry. Uterine samples were removed at various times after hormone administration and changes in wingless (Wnt) pathway effectors and gene targets were identified by microarray. Progesterone pretreatment decreased glycogen synthase kinase-3beta (GSK-3beta) and increased expression of T-cell factor/lymphoid enhancer factor (TCF/LEF). GSK-3beta protein decreased markedly in the uterine stroma of progesterone-pretreated uteri with the concomitant appearance of beta-catenin in these stromal cells. Translocation of beta-catenin from the cytosol to the nuclei in progesterone-pretreated stromal cells was stimulated in response to estradiol. Beta-catenin binding to TCF/LEF increased (P<0.05) in progesterone-pretreated uteri in response to estradiol. Progesterone stimulated the expression of the Wnt target gene urokinase plasminogen activator receptor (uPA-R) in the periluminal uterine stromal cells. The expression of uPA-R increased in progesterone-pretreated stromal cells in response to estradiol administration. Together, the results indicate that progesterone initiates Wnt signaling in the uterine stroma by down-regulating GSK-3beta. However, nuclear translocation of beta-catenin and sufficient complex formation with TCF/LEF to activate stromal cell cycle entry requires estradiol. Stimulation of a uterine stromal cell line to proliferate and differentiate resulted in beta-catenin accumulation, suggesting that endocrine-dependent Wnt signaling controls proliferation and differentiation (decidualization).

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