Abstract
Aberrant regulation of uterine cell growth can lead to endometrial cancer and infertility. To understand the molecular mechanisms of estrogen-induced uterine cell growth, we removed the estrogen receptor α (Esr1) from mouse uterine stromal cells, where the embryo is implanted during pregnancy. Without ESR1 in neighboring stroma cells, epithelial cells that line the inside of the uterus are unable to grow due to a lack of growth factors secreted from adjacent stromal cells. Moreover, loss of stromal ESR1 caused mice to deliver fewer pups due in part due to inability of some embryos to implant in the uterus, indicating that stromal ESR1 is crucial for uterine cell growth and pregnancy.
Highlights
Estrogens induce cell proliferation and growth in both reproductive and non-reproductive tissues
No E2 induced epithelial proliferation occurs in global Esr1-null uteri[21], demonstrating that uterine ESR1 is needed to mediate epithelial proliferation, we hypothesized that stromal ESR1 was required for paracrine regulation of epithelial cell proliferation
We previously reported that several genes associated with cell-cycle progression, including Igf[1], CCAAT enhancer binding protein beta (Cebpb), cyclin-dependent kinase inhibitor 1a (Cdkn1a), and mitotic arrest deficient 2-like protein 1 (Mad2l1), were E2 responsive genes and that their expression was epithelial ESR1-independent, potentially mediated by stromal ESR18, 22
Summary
Estrogens induce cell proliferation and growth in both reproductive and non-reproductive tissues (such as osteoblasts and hepatocytes). Tissue recombination studies using isolated epithelial and stromal cells from wild-type or Esr1−/− neonatal uterine tissues transplanted under the kidney capsule showed that ESR1 is not required in uterine epithelial cells for their proliferation We have confirmed this observation using an adult epithelial cell specific knockout mouse model (Wnt7aCre/+; Esr1f/f)[7, 8], with an intact (no tissue disruption and recombination) uterine tissue structure. Using a female reproductive tract epithelial cell ESR1 null mouse model (Wnt7aCre/+; Esr1f/f), our group and others have demonstrated that uterine epithelial ESR1 is crucial for embryo implantation, decidual response, and fertility[8, 17]. Stromal ESR1 in the uterine anti-mesometrium is crucial for optimal embryo implantation and artificially induced-decidualization
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