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Title:Estrogen signaling during decidualization
Author(s):Das, Amrita
Director of Research:Bagchi, Indrani C.
Doctoral Committee Chair(s):Bagchi, Indrani C.
Doctoral Committee Member(s):Bagchi, Milan K.; Flaws, Jodi A.; Yao, Humphrey H-C.
Department / Program:Veterinary Biosciences
Discipline:VMS - Veterinary Biosciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Abstract:The process of implantation begins with the attachment of the embryo to the uterine lumen. This event is followed by the development of the implanted blastocyst in the differentiated endometrium. Decidualization, a signatory event during this process is characterized by the deciduous transformation of fibroblast endometrial stromal cells to morphologically and functionally unique decidual cells along with the formation of extensive neo-angiogenic networks that play pivotal role in nourishing the developing embryo. Steroid hormones estrogen (E) and progesterone (P) acting through their cognate nuclear receptors critically modulate this maternal-fetal interaction that entails the initial success of procreation. While E is primarily involved in cell proliferation and acquisition of epithelial receptivity, P critically governs stromal differentiation in addition to contributing to E action in preparing the uterus prior to the attachment reaction. Thus, a thriving implantation is the manifestation of complementary steroid hormone action both during the proliferation and differentiation phases. The role of E in decidualization however remained elusive. Our studies indicated that the decidual uterus harbors steroid biosynthetic machinery driving the local production of intra-uterine E in both mouse and human endometrium. This local steroid acting through the estrogen receptor alpha (ERα) plays a major role in sustaining decidualization and uterine vascularization, absence of which resulted in embryo resorption. To identify the downstream signaling pathway(s) and molecular candidate(s) that mediate the action of local E, we performed gene expression profiling, using decidual tissues obtained from mice treated with or without letrozole, a specific inhibitor to the key biosynthetic enzyme, cytochrome P450 aromatase. Of the number of molecules identified from the microarray analysis likely to be involved in cell differentiation, the c-Fos family member Fos related antigen-1 (FRA-1), was significantly regulated by local E. Our studies further revealed that FRA-1 is a direct target of the E/ERα signaling in the decidual uterus and plays a major role in sustaining the stromal differentiation process. FRA-1, which exhibits strong nuclear expression in the uterine decidual cells, also governed the extent of embryo invasion by modulating the stromal cell migration and remodeling. Additionally gene profiling experiments indicated that uterine E regulated the development of vascular network via the expression of cytokines and paracrine factors from the differentiated stroma. To understand the direct implication of this study in reproductive health of adult individuals, we next monitored the presence of endogenous E signaling in the human endometrium using primary stromal cells isolated from endometrial biopsies of healthy females. In this in vitro model system, decidualization can be induced by administering a cocktail of steroid hormones and cAMP. We were able to demonstrate significant induction of aromatase in the differentiating cells which resulted in local biosynthesis of E. Further, siRNA mediated gene silencing of aromatase or ERα expression led to a significant down regulation of human endometrial decidual bio-markers, indicating a major contribution of this intra-uterine E signaling in mediating stromal cell differentiation. Together, this study has helped us to gain novel insights of steroid hormone regulation of endometrial stromal cell differentiation and angiogenesis in mouse and human implantation.
Issue Date:2010-05-14
Rights Information:Copyright 2010 Amrita Das
Date Available in IDEALS:2010-05-14
Date Deposited:May 2010

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