Implantation of the human embryo requires Rac1-dependent endometrial stromal cell migration

Abstract

Failure of the human embryo to implant into the uterine wall during the early stages of pregnancy is a major cause of infertility. Implantation involves embryo apposition and adhesion to the endometrial epithelium followed by penetration through the epithelium and invasion of the embryonic trophoblast through the endometrial stroma. Although gene-knockdown studies have highlighted several molecules that are important for implantation in the mouse, the molecular mechanisms controlling implantation in the human are unknown. Here, we demonstrate in an in vitro model for human implantation that the Rho GTPases Rac1 and RhoA in human endometrial stromal cells modulate invasion of the human embryo through the endometrial stroma. We show that knockdown of Rac1 expression in human endometrial stromal cells inhibits human embryonic trophoblast invasion into stromal cell monolayers, whereas inhibition of RhoA activity promotes embryo invasion. Furthermore, we demonstrate that Rac1 is required for human endometrial stromal cell migration and that the motility of the stromal cells increases at implantation sites. This increased motility correlates with a localized increase in Rac1 activation and a reciprocal decrease in RacGAP1 levels. These results reveal embryo-induced and localized endometrial responses that may govern implantation of the human embryo.human trophoblast invasion ͉ implantation in vitro ͉ Rac-1 activation ͉ RacGAP1 ͉ Rho GTPases

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

“…Moreover, its coupling with TNFα-P38 signaling cascade ensures normal epithelial apoptotic elimination at postimplantation. Our findings have high clinical relevance, because Rac1 is essential for normal human endometrial-embryo dialogue as well as implantation, 23 and Ezrin has been reported to be mislocalized in the mid-secretory phase in infertile women. 63 Materials and Methods Animals and treatments.…”

“…Because Ras-related C3 botulinum toxin substrate 1 (Rac1), a small GTPase belonging to the 21 kDa Rho-GTPase family, 16,17 is a multifunctional switch involved in epithelial development, differentiation and apoptotic cell clearance in various systems, [18][19][20][21][22] and Rac1 is also involved in regulating human endometrial stromal cell migration in culture, 23 we speculated that Rac1 and its driving signaling cascade might be an important player directing normal luminal epithelial integrity conducive to on-time embryo implantation. To address this issue, in the present study, we used a uterine Rac1 conditional deletion mouse model and demonstrated that Rac1 depletion in the uterus induces premature decrease of epithelial apical-basal polarity and defective junction remodeling, hampering normal uterine receptivity and thus on-time embryo implantation.…”

Clinical significance of RacGAP1 expression at the invasive front of gastric cancer

“…Epithelial-mesenchymal transition (EMT) is known to be one potential mechanism of migration, invasion and metastasis of cancer cells including gastric cancer [32,33]. RacGAP1 regulates the function of Rho proteins such as Rac and cdc42 to influence cell morphology, cell motility, and the establishment of cell polarity and consequently plays a key role in metastasis [9,34]. Zondag et al [35] showed that the interaction between Rho and Rac GTPases and the downregulation of Rac activity led to increased Rho activity and EMT.…”

High-Risk Endometrial Carcinoma Profiling Identifies TGF-β1 as a Key Factor in the Initiation of Tumor Invasion

“…Interestingly, the majority of the genes at the core of the molecular network related to high risk of recurrence in endometrial carcinoma refer to the process of trophoblast invasion. Genes such as FOS, MMP9, MAPK1, RHOA, and TGF-b1 have been described as main directors of the process of embryo implantation (27,28). In fact, the molecular events characterizing trophoblast implantation as a physiological process of invasion into the uterus, strictly controlled both at the time and space levels, have been paralleled to the process of endometrial tumor invasion in an uncontrolled manner (29).…”