Journal
MOLECULAR HUMAN REPRODUCTION
Volume 20, Issue 8, Pages 776-786Publisher
OXFORD UNIV PRESS
DOI: 10.1093/molehr/gau033
Keywords
transforming growth factor beta; uterus; epithelial cell; proliferation; endometrial hyperplasia
Funding
- National Institutes of Health from the Eunice Kennedy Shriver National Institute of Child Health & Human Development [R21HD073756]
- Ralph E. Powe Junior Faculty Enhancement Awards from Oak Ridge Associated Universities
- New Faculty Start-up Funds from Texas AM University
- College of Veterinary Medicine graduate student research award from Texas AM University
- China Scholarship Council
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In the uterus, epithelial cell proliferation changes during the estrous cycle and pregnancy. Uncontrolled epithelial cell proliferation results in implantation failure and/or cancer development. Transforming growth factor-beta (TGF-beta) signaling is a fundamental regulator of diverse biological processes and is indispensable for multiple reproductive functions. However, the in vivo role of TGF-beta signaling in uterine epithelial cells remains poorly defined. We have shown that in the uterus, conditional deletion of the Type 1 receptor for TGF-beta (Tgfbr1) using anti-Mullerian hormone receptor type 2 (Amhr2) Cre leads to myometrial defects. Here, we describe enhanced epithelial cell proliferation by immunostaining of Ki67 in the uteri of these mice. The aberration culminated in endometrial hyperplasia in aged females. To exclude the potential influence of ovarian steroid hormones, the proliferative status of uterine epithelial cells was assessed following ovariectomy. Increased uterine epithelial cell proliferation was also revealed in ovariectomized Tgfbr1 Amhr2-Cre conditional knockout mice. We further demonstrated that transcript levels for fibroblast growth factor 10 (Fgf10) were markedly up-regulated in Tgfbr1 Amhr2-Cre conditional knockout uteri. Consistently, treatment of primary uterine stromal cells with TGF-beta 1 significantly reduced Fgf10 mRNA expression. Thus, our findings suggest a potential involvement of TGFBR1-mediated signaling in the regulation of uterine epithelial cell proliferation, and provide genetic evidence supporting the role of uterine epithelial cell proliferation in the pathogenesis of endometrial hyperplasia.
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