Abstract
BackgroundThe establishment of uterine receptivity is essential for embryo implantation initiation and involves a significant morphological transformation in the endometrial epithelial cells (EECs). The remodeling of junctional complexes and membrane-associated cytoskeleton is crucial for epithelial transformation. However, little is known about how this process is regulated in EECs during the receptive phase. ARHGAP19 is a Rho GTPase-activating protein that participates in various cytoskeletal-related events, including epithelial morphogenesis. Here, we investigated the role of ARHGAP19 in endometrial epithelial transformation during the establishment of uterine receptivity. The upstream regulator of ARHGAP19 was also investigated.MethodsARHGAP19 expression was examined in mouse uteri during early pregnancy and in human EEC lines. The role of ARHGAP19 was investigated by manipulating its expression in EECs. The effect of ARHGAP19 on junctional proteins in EECs was examined by western blotting and immunofluorescence. The effect of ARHGAP19 on microvilli was examined by scanning electron microscopy. The upstream microRNA (miRNA) was predicted using online databases and validated by the dual-luciferase assay. The in vivo and in vitro effect of miRNA on endogenous ARHGAP19 was examined by uterine injection of miRNA agomirs and transfection of miRNA mimics or inhibitors.ResultsARHGAP19 was upregulated in the receptive mouse uteri and human EECs. Overexpression of ARHGAP19 in non-receptive EECs downregulated the expression of junctional proteins and resulted in their redistribution. Meanwhile, upregulating ARHGAP19 reorganized the cytoskeletal structure of EECs, leading to a decline of microvilli and changes in cell configuration. These changes weakened epithelial cell polarity and promoted the transition of non-receptive EECs to a receptive phenotype. Besides, miR-192-5p, a miRNA that plays a key role in maintaining epithelial properties, was validated as an upstream regulator of ARHGAP19.ConclusionThese results suggested that ARHGAP19 may contribute to the transition of EECs from a non-receptive to a receptive state by regulating the remodeling of junctional proteins and membrane-associated cytoskeleton.
Highlights
The establishment of uterine receptivity is essential for embryo implantation initiation and involves a significant morphological transformation in the endometrial epithelial cells (EECs)
Through manipulating ARHG AP19 expression in EECs, we showed that upregulating ARHGAP19 promotes the transition of EECs from a non-receptive phenotype to a receptive phenotype by regulating the remodeling of junctional complex and cytoskeletal structures
Implantation sites (IMS) on D5 were visualized by intravenous injection of 0.1 ml of 1% Chicago blue (Sigma, St Louis, MO, USA) [11], and the uterine tissue between two implantation sites was designated as inter-implantation sites (IIS)
Summary
The establishment of uterine receptivity is essential for embryo implantation initiation and involves a significant morphological transformation in the endometrial epithelial cells (EECs). The apical surface of non-receptive EECs is covered with actin-containing microvilli and does not exhibit adhesive properties [5]. These features of epithelial cells make the luminal epithelium a barrier for blastocyst adhesion and invasion. Accumulating evidence suggests that the remodeling of junctional complexes and the reorganization of actin cytoskeleton are key factors that regulate morphological changes in cells, and cytoskeletal regulators, such as Rho-family GTPases as well as their regulators contribute significantly in this process [7, 8]. Little is known about how these cytoskeleton regulators behave during epithelial transformation in establishing uterine receptivity
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