Date of Award

5-1-2013

Degree Name

Doctor of Philosophy

Department

Molecular, Cellular, and Systemic Physiology

First Advisor

Bany, Brent

Abstract

Blastocyst implantation is the process in which a competent blastocyst acquires the ability to tether into the mother endometrium. At the same time, the endometrial tissue undergoes the process of decidualization to support the anchoring of the blastocyst and provides the blastocyst with nutrition until the fully functional placenta is formed. Although the process of implantation and decidualization are under control of progesterone and estrogen, the precise mechanisms involved in this regulation are not fully understood. Here, we report the expression and function of a transcription factor, HAND2, in sensitizing mouse uterus for implantation and decidualization. In mouse, HAND2 expression was localized mainly in the endometrial stromal cells even before the blastocyst implantation. The expression of HAND2 increased after blastocyst implantation and correlated with the increase in decidual compartment. The expression of HAND2 depended on progesterone but not estrogen. Further investigation using conditional knockout mouse revealed that HAND2 was important for both implantation and decidualization. Hand2d/d mice were infertile and had defects in decidualization. It seemed that HAND2 was an important factor that mediates the anti-estrogenic effect of progesterone on luminal epithelial proliferation. The abnormal in expression of Mucin 1, Calcitonin and E-Cadherin in Hand KO uterus may be responsible for defects in the uterine receptivity. The expression of HAND2 was also critical in decidualization in vitro. Silencing and over-expression HAND2 disclosed the roles of HAND2 in regulating the expression of FOXO1A, IGFBP1, BMP2 as well as WNT4. It seemed that HAND2 promoter worked in tissue specific manner and although both HOXA10 and cAMP binding sites were found in proposed HAND2 promoters, its activity was stimulated by cAMP and steroid hormones rather than the expression of HOXA10.

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