Date of Award

5-1-2012

Degree Name

Master of Science

Department

Molecular Cellular and Systemic Physiology

First Advisor

Hayashi, Kanako

Abstract

E–cadherin (CDH1) is a cell–cell adhesion molecule expressed in the epithelium to coordinate key morphogenetic processes, establish cell polarity, and regulate epithelial differentiation and proliferation. CDH1 forms adherens junctions that mediate intercellular adhesion through dynamic interactions with β–catenin (CTNNB1). To determine the role of CDH1 in the mouse uterus, Cdh1 was conditionally ablated by crossing Pgr–Cre and Cdh1–flox mice. Animals with the resulting genotype of Pgrcre/+Cdh1f/f had Cdh1 conditionally ablated in the Pgr expressing tissue, which includes the uterus (referred to as Cdh1d/d). We characterized the phenotype and found that loss of Cdh1 in the neonatal uterus results in a disorganized cellular structure of the epithelium and ablation of endometrial glands. Cdh1d/d mice lost adherens junction (CTNNB1 and CTNNA1) and tight junction (claudin, occludin and ZO–1) in the neonatal uterus leading to loss of epithelial cell–cell interaction. Ablation of Cdh1 induced abnormal epithelial proliferation and massive apoptosis, and disrupted Wnt and Hox gene expression in the neonatal uterus. Although the uteri of Cdh1d/d mice did not show any defect of myometrium, ablation of Cdh1 inhibited stromal (CD10) markers. In addition, a conditional knockout of Ctnnb1 in the uterus and a double conditional knockout of Cdh1&Ctnnb1 in the uterus were created to determine if the uterine defects were caused by an alteration in CDH1, CTNNB1, or a combination of both. Ctnnb1 and Cdh1&Ctnnb1 were conditionally ablated in the uterus by crossing Pgr–Cre and Ctnnb1–flox mice or Cdh1&Ctnnb1–flox mice. The Ctnnb1d/d mice maintained adhesive epithelial characteristics and did not lose adherens junction or tight junction proteins; however ablation of Ctnnb1 induced epithelial hyperplasia and disrupted Wnt and Hox gene expression in the neonatal uterus. The Cdh1d/dCtnnb1d/d mice carried a similar phenotype to the Cdh1d/d mice. Adult Cdh1d/d mice were infertile due to defects during implantation and decidualization. Collectively, these findings suggest that CDH1 has an important role in structural and functional development of the uterus as well as adult uterine function. CDH1 has a capacity to control cell fate by altering directional cell proliferation and apoptosis.

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