Language

English

Publication Date

12-9-2025

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2518507122

PMID

41337483

PMCID

PMC12704753

PubMedCentral® Posted Date

12-3-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Proper endometrial function is critical for establishing and maintaining healthy pregnancies, as well as preventing the pathogenesis of conditions such as endometrial hyperplasia and endometrial cancer. The TGFβ signaling pathway regulates key aspects of endometrial biology, although the direct effects of many individual receptors remain unstudied. In this study, we characterize the role of TGFβR2 within the endometrium using a progesterone receptor-cre conditional knock-out mouse model (Tgfbr2flox/flox;Pgrcre/+; “Tgfbr2 cKO”). We found that conditional deletion of TGFβR2 resulted in female infertility, endometrial hyperplasia, altered estrogen and progesterone response, and, only in bred females, reproductive tract tumors. Pregnancy abnormalities in these females began in the prereceptive and implantation stages and compounded throughout gestation, presenting errors in decidualization, immune cell invasion, and early spiral artery formation. Tgfbr2 cKO females had endometrial epithelial hyperplasia at 13 to 14 wk of age, with a significant and region-specific reduction in glandular FOXA2 expression. While this hyperplasia did not advance to malignancy in virgin females, Tgfbr2 cKO females continuously bred for 6 mo all presented with reproductive tract tumors at the time of collection. Mechanistically, we show signaling via TGFβR2 attenuates estrogen signaling while bolstering progesterone signaling in the endometrial epithelium. By integrating ER and SMAD4 genome-wide binding studies with transcriptomic datasets, we demonstrate that both ER and SMAD4 are required for Pgr transcription. In this study, we highlight the importance of TGFβR2 in endometrial function and female fertility and shed light on the potential involvement of TGFβ signaling in estrogen and progesterone response regulation during early pregnancy.

Keywords

Female, Animals, Endometrial Hyperplasia, Mice, Estrogens, Endometrium, Receptor, Transforming Growth Factor-beta Type II, Mice, Knockout, Fertility, Pregnancy, Signal Transduction, Receptors, Progesterone, Infertility, Female, Progesterone, endometrium, organoids, endometrial hyperplasia, estrogen response, pregnancy

Published Open-Access

yes

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