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    Silencing H19 regulated proliferation, invasion, and autophagy in the placenta by targeting miR-18a-5p. Zhang Lei,Deng Xinru,Shi Xian,Dong Xiaojing Journal of cellular biochemistry Fetal growth restriction (FGR) is a serious pregnancy complication associated with increased perinatal mortality and morbidity. It may lead to neurodevelopmental impairment and adulthood onset disorders. Recently, long noncoding RNAs (lncRNAs) were found to be associated with the pathogenesis of FGR. Here we report that the lncRNAH19 is significantly decreased in placentae from pregnancies with FGR. Downregulation of H19 leads to reduced proliferation and invasion of extravillous trophoblast cells. This is identified with reduced trophoblast invasion, which has been discovered in FGR. Autophagy is exaggerated in FGR. Downregulation of H19 promotes autophagy via the PI3K/AKT/mTOR and MAPK/ERK/mTOR pathways of extravillous trophoblast cells in FGR. We also found that the expression level of microRNAs miR-18a-5p was negatively correlated with that of H19. H19 can act as an endogenous sponge by directly binding to miR-18a-5p, which targets IRF2. The expression of miR-18a-5p was upregulated, but IRF2 expression was downregulated after the H19 knockdown. In conclusion, our study revealed that H19 downexpressed could inhibit proliferation and invasion, and promote autophagy by targeting miR-18a-5pin HTR8 and JEG3 cells. We propose that aberrant regulation of H19/miR-18a-5p-mediated regulatory pathway may contribute to the molecular mechanism of FGR. We indicated that H19 may be a potential predictive, diagnostic, and therapeutic modality for FGR. 10.1002/jcb.28172
    MEF2 transcription factors in human placenta and involvement in cytotrophoblast invasion and differentiation. Li Lucy,Rubin Lewis P,Gong Xiaoming Physiological genomics Development of the human placenta and its trophoblast cell types is critical for a successful pregnancy. Defects in trophoblast invasion and differentiation are associated with adverse pregnancy outcomes, including preeclampsia. The members of myocyte enhancer factor-2 (MEF2) family of transcription factors are key regulators of cellular proliferation, differentiation, and invasion in various cell types and tissues and might play a similarly important role in regulating trophoblast proliferation, invasion, and differentiation during human placental development. In the present study, using human cytotrophoblast cell lines (HTR8/SVneo and BeWo) and primary human cytotrophoblasts (CTBs), we show that members of the MEF2 family are differentially expressed in human placental CTBs, with MEF2B and MEF2D being highly expressed in first trimester extravillous CTBs. Overexpression of MEF2D results in cytotrophoblast proliferation and enhances the invasion and migration of extravillous-like HTR8/SVneo cells. This invasive property is blocked by overexpression of a dominant negative MEF2 (dnMEF2). In contrast, MEF2A is the principal MEF2 isoform expressed in term CTBs, MEF2C and MEF2D being expressed more weakly, and MEF2B expression being undetected. Overexpression of MEF2A induces cytotrophoblast differentiation and syncytium formation in BeWo cells. During in vitro differentiation of primary CTBs, MEF2A expression is associated with CTB differentiation into syncytiotrophoblast. Additionally, the course of p38 MAPK and ERK5 activities parallels the increase in MEF2A expression. These findings suggest individual members of MEF2 family distinctively regulate cytotrophoblast proliferation, invasion, and differentiation. Dysregulation of expression of MEF2 family or of their upstream signaling pathways may be associated with placenta-related pregnancy disorders. 10.1152/physiolgenomics.00076.2017
    Implication of MEK1 and MEK2 in the establishment of the blood-placenta barrier during placentogenesis in mouse. Charron Jean,Bissonauth Vickram,Nadeau Valérie Reproductive biomedicine online The ERK/MAPK signalling cascade is involved in many cellular functions. In mice, the targeted ablation of genes coding for members of this pathway is often associated with embryonic death due to the abnormal development of the placenta. The placenta is essential for nutritional and gaseous exchanges between maternal and embryonic circulations, as well as for the elimination of metabolic waste. These exchanges occur without direct contact between the two circulations. In mice, the blood-placenta barrier consists of a triple layer of trophoblast cells adjacent to endothelial cells from the embryo. In the ERK/MAPK cascade, MEK1 and MEK2 are dual-specificity kinases responsible for the activation of the ERK1 and ERK2 kinases. Inactivation of Mek1 causes placental malformations resulting from defective proliferation and differentiation of the labyrinthine trophoblast cells and leading to a severe delay in the development and the vascularization of the placenta, which explains the embryonic death. Although Mek2(-/-) mutants survive without any apparent phenotype, a large proportion of Mek1(+/-)Mek2(+/-) double heterozygous mutants die during gestation from placenta anomalies affecting the establishment of the blood-placenta barrier. Together, these data reveal how crucial is the role of the ERK/MAPK pathway during the formation of the placenta. 10.1016/j.rbmo.2012.02.012