Journal article
Uterine epithelial estrogen receptor α is dispensable for proliferation but essential for complete biological and biochemical responses
Proceedings of the National Academy of Sciences - PNAS, Vol.107(45), pp.19272-19277
11/09/2010
Handle:
https://hdl.handle.net/2376/115441
PMCID: PMC2984169
PMID: 20974921
Abstract
Female fertility requires estrogen to specifically stimulate estrogen receptor α (ERα)-dependent growth of the uterine epithelium in adult mice, while immature females show proliferation in both stroma and epithelium. To address the relative roles of ERα in mediating estrogen action in uterine epithelium versus stroma, a uterine epithelial-specific ERα knockout (UtEpiαERKO) mouse line was generated by crossing
Esr
mice with
Wnt7a
-Cre mice. Expression of
Wnt7a
directed Cre activity generated selective deletion of ERα in uterine epithelium, and female UtEpiαERKO are infertile. Herein, we demonstrate that 17β-estradiol (
E
2
)-induced uterine epithelial proliferation was independent of uterine epithelial ERα because DNA synthesis and up-regulation of mitogenic mediators were sustained in UtEpiαERKO uteri after
E
2
treatment. IGF-1 treatment resulted in ligand-independent ER activation in both wild-type (WT) and UtEpiαERKO and mimicked the
E
2
stimulatory effect on DNA synthesis in uterine epithelium. Uterine epithelial ERα was necessary to induce lactoferrin, an
E
2
-regulated secretory protein selectively synthesized in the uterine epithelium. However, loss of uterine epithelial ERα did not alter the
E
2
-dependent progesterone receptor (PR) down-regulation in epithelium. Strikingly, the uterine epithelium of UtEpiαERKO had robust evidence of apoptosis after 3 d of
E
2
treatment. Therefore, we surmise that estrogen induced uterine hyperplasia involves a dispensable role for uterine epithelial ERα in the proliferative response, but ERα is required subsequent to proliferation to prevent uterine epithelial apoptosis assuring the full uterine epithelial response, illustrating the differential cellular roles for ERα in uterine tissue and its contribution during pregnancy.
Metrics
8 Record Views
Details
- Title
- Uterine epithelial estrogen receptor α is dispensable for proliferation but essential for complete biological and biochemical responses
- Creators
- Wipawee Winuthayanon - Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709Sylvia C Hewitt - Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709Grant D Orvis - Developmental Biology Program, Sloan–Kettering Institute, York Avenue, New York, NY 10065; andRichard R Behringer - Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030Kenneth S Korach - Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.107(45), pp.19272-19277
- Academic Unit
- Molecular Biosciences, School of
- Publisher
- National Academy of Sciences
- Identifiers
- 99900547758801842
- Language
- English
- Resource Type
- Journal article