Implantation of the embryo into the wall of the uterus is a crucial event in mammalian embryogenesis. This complex event involves a series of interactions between the developing embryo and the receptive endometrium ultimately leading to successful establishment of pregnancy. The sequential events of implantation include apposition of the blastocyst to the uterine luminal epithelium followed by adhesion to the epithelium and then penetration through the epithelium and basal lamina into the uterine stroma. Uterine sensitivity with respect to implantation has been classified as prereceptive, receptive, and nonreceptive phases. In the mouse, day 1–3 of pregnancy constitutes the prereceptive phase and day 4 is considered receptive. The window of uterine receptivity is transient and lasts for a limited time. On day 5 of pregnancy, the uterus is nonreceptive or refractory. Studies over the past decade have identified a variety of molecules including growth factors, cytokines, transcription factors, and extracellular matrix proteins as potential regulators of this complex process. This dissertation work investigates the critical role of Msx homeobox genes in the uterus during embryo implantation. The mammalian Msx homeobox genes, Msx1 and Msx2, encode transcription factors that control organogenesis and tissue interactions during embryonic development. Uterine specific deletion of Msx1 and Msx2 resulted in female infertility due to a failure in implantation. Further analysis indicated that mice lacking uterine Msx1 and Msx2 (Msx1d/dMsx2d/d) exhibited a failure in uterine receptivity due to enhanced estrogen signaling in the luminal epithelium, failure of microvilli remodeling, sustained epithelial cell polarity and persistent proliferative activity of luminal and glandular epithelium. More recent studies revealed that canonical Wnt/ β-catenin signaling were upregulated in the Msx1Msx2-null uteri, which in turn stimulated the production of a subset of fibroblast growth factors (FGFs) in the stromal cells. The FGFs subsequently activate FGFR-ERK-MAP kinase signaling pathway in the luminal epithelium resulting in sustained epithelial cellular proliferation. These results uncovered a unique signaling network, involving Msx1/2, Wnts, and FGFs, which regulate stromal-epithelial cross talk in the mouse uterus at the time of receptivity. The last chapter addresses the role of Msx homeobox genes during uterine stromal cell decidualization. As the embryo attaches to the uterine wall and invades into the stromal bed, the stromal cells surrounding the implanting blastocyst differentiate into decidual cells in a process known as decidualization. This process is critical for embryo survival, angiogenesis and successful establishment of pregnancy. We previously reported that Bone morphogenetic protein 2 (BMP2) regulates uterine stromal cell differentiation in the mouse and the human. Subsequent studies revealed that the expressions of Msx1 and Msx2 were markedly altered in response to exogenous BMP2. Functional studies performed using Msx1d/dMsx2d/d mice revealed that mouse uteri lacking Msx1 and Msx2 fail to elicit a decidual response, indicating a critical role of these homeobox genes in stromal cell differentiation. Further studies revealed that the addition of BMP2 stimulated MSX1 and MSX2 expression in human endometrial stromal cell cultures and enhanced the differentiation process. Silencing of MSX1 or MSX2 expression by siRNAs severely impaired human stromal differentiation indicating that MSX1 and MSX2 are key regulators of BMP2-mediated decidualization in the mouse and the human.
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Role of Msx homeobox genes in uterus during embryo implantation
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