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Title:Molecular mechanisms regulating implantation
Author(s):Pawar, Sandeep
Director of Research:Bagchi, Milan K.
Doctoral Committee Chair(s):Bagchi, Milan K.
Doctoral Committee Member(s):Bagchi, Indrani C.; Katzenellenbogen, Benita S.; Raetzman, Lori T.; Bolton, Eric C.
Department / Program:Molecular & Integrative Physl
Discipline:Molecular & Integrative Physi
Degree Granting Institution:University of Illinois at Urbana-Champaign
Epithelial-Stromal interaction
Abstract:Implantation, a critical early event during pregnancy, is a three stage process. It starts with apposition and adhesion of the blastocyst to a receptive uterine epithelium which is then followed by invasion of the blastocyst into a decidualizing stroma. These stages are tightly regulated by steroid hormones Estrogen (E) and Progesterone (P). Genomic profiling in mice has uncovered novel steroid regulated genes in the uterine luminal epithelium and also in the stroma which regulate implantation. Recent evidence also points to the fact that stromal-epithelial interactions are critical for a successful implantation. To understand the mechanisms governing these complex interactions and better address the clinical challenges to infertility, it is important to integrate the information gained from these studies. Chapter I presents a detailed analysis of the knowledge gained from reviewing these studies. Estrogen acts via its cognate steroid hormone receptor, estrogen receptor alpha (ESR), in order to exert its effects during pregnancy. The studies reported here investigate E’s action via ESR1 and its downstream targets in uterine physiology and is written in three parts. The first part is an investigation of role of epithelial ESR1in the uterus during stromal cell decidualization. Earlier studies in our lab had indicated an essential role of uterine ESR1 in stromal cell decidualization. This study prompted an investigation into the compartment specific role of ESR1 in uterine stromal cell decidualization. We have used an epithelial specific knockout mouse of Esr1 known as WEd/d in order to analyse the role of epithelial ESR1 in this process. Our investigation has provided novel insights into a paracrine mechanism of action in which Epithelial ESR1 controls stromal cell decidualization via Leukaemia Inhibitory Factor (LIF) and Indian Hedgehog (IHH). The second part of this study investigates the role of signal transducer and activator of transcription 3 (STAT3) in the uterine epithelial cells during implantation. STAT3 is activated downstream of LIF, an E target gene, in the uterine epithelial cells during the window of implantation. To identify the molecular pathways regulated by STAT3, we created SWd/d mice in which Stat3 gene is conditionally inactivated in uterine epithelium. These mutant mice are infertile and exhibit embryo implantation and uterine stromal cell decidualization defect. Further analysis revealed dysregulation of several junctional complexes in the luminal epithelial cells of SWd/d mice during the window of implantation which adversely affects uterine receptivity and embryo attachment. Additionally, epithelial STAT3 also controlled certain aspects of stromal cell decidualization by inducing the expression of epidermal growth factor (EGF) production in the luminal epithelium during implantation. A decrease in EGF production adversely affects stromal cell proliferation. Our results uncovered an intricate genetic network operating downstream of STAT3 that regulates uterine epithelial junctional reorganization, stromal proliferation and differentiation, which are critical determinants of successful implantation. In the fourth chapter of this thesis we describe our ongoing studies investigating the role of an E target gene, endothelial PAS domain – 1 in uterine decidual angiogenesis. Our laboratory has shown that it is local E production acting via ESR1 within the uterine stromal cells that drives and sustains the decidualization response. Furthermore this local E production regulates EPAS-1, also called hypoxia-inducible factor 2 alpha (Hif2). EPAS-1 is a transcription factor that has been shown to be regulated by hypoxic conditions and regulates molecules essential for an angiogenesis response. In order to study the functional role of EPAS-1we have created a conditional knockout of the EPAS-1, which has EPAS-1 knocked out in all cells expressing PGR. This conditional knockout mouse, termed Epas-1d/d, is infertile. Further analysis revealed that without EPAS-1in the stromal cells, angiogenesis at the early stages of pregnancy is impaired as marked by a downregulation of an endothelial cell marker, PECAM. Understanding downstream molecules of EPAS-1will undoubtedly give insight into the molecular pathways essential for uterine decidual angiogenesis.
Issue Date:2014-05-30
Rights Information:Copyright 2014 Sandeep Pawar
Date Available in IDEALS:2014-05-30
Date Deposited:2014-05

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