Decreased Placental GCM1 (Glial Cells Missing) Gene Expression in Pre-eclampsia

Chen, C.-P.; Chen, C.-Y.; Yang, Yuh Cheng; Su, Ta‐Wei; Chen, H.

doi:10.1016/j.placenta.2003.10.014

Cited by 103 publications

(95 citation statements)

References 25 publications

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“…In the related disorder of severe earlyonset preeclampsia, GCM1 is significantly downregulated. 14 Furthermore, immunohistochemical and morphometric analyses of preeclamptic placentae revealed an increase in proliferative activity of cytotrophoblast. 31,32 Therefore, these diseases might represent divergent end points resulting from Understanding the mechanisms that govern CT cell survival in the human placenta, and the selective expression of GCM1 in CT destined for syncytial fusion or in EV-CT remodeling spiral arteries will improve our perception of the early origins of severe IUGR and preeclampsia caused by the so-called 'placental insufficiency.'…”

Section: Discussionmentioning

confidence: 99%

“…13 Both GCM1 and Syncytin1 are reduced in preeclampsia and HELLP (Hemolysis Elevated Liver enzymes and Low Platelet count) syndrome and may, therefore, be important contributors to this type of placental insufficiency. 14,15 Understanding the molecular mechanisms that regulate human trophoblast proliferation and differentiation is key to our perception of severe placental pathologies of pregnancy. Using a human-derived BeWo choriocarcinoma cell line, and first trimester human villous and extravillous placental explant models, we show a central role for GCM1 in the regulation of key aspects of human placental development specifically with respect to (1) cytotrophoblast proliferation, (2) villous syncytial fusion and (3) extravillous trophoblast differentiation.…”

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Glial cell missing-1 transcription factor is required for the differentiation of the human trophoblast

et al. 2009

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Mammalian placentation is a highly regulated process and is dependent on the proper development of specific trophoblast cell lineages. The two major types of trophoblast, villous and extravillous, show mitotic arrest during differentiation. In mice, the transcription factor, glial cell missing-1 (Gcm1), blocks mitosis and is required for syncytiotrophoblast formation and morphogenesis of the labyrinth, the murine equivalent of the villous placenta. The human homolog GCM1 has an analogous expression pattern, but its function is presently unknown. We studied GCM1 function in the human-derived BeWo choriocarcinoma cell line and in first trimester human placental villous and extravillous explants. The GCM1 expression was either inhibited by siRNA and antisense oligonucleotides methods or upregulated by forskolin treatment. Inhibition of GCM1 resulted in an increased rate of proliferation, but prevented de novo syncytiotrophoblast formation in syncytially denuded floating villous explants. GCM1 inhibition prevented extravillous differentiation along the invasive pathway in extravillous explants on matrigel. By contrast, forskolin-induced expression of GCM1 reduced the rate of proliferation and increased the rate of syncytialization in the floating villous explant model. Our studies show that GCM1 has a distinct role in the maintenance, development and turnover of the human trophoblast. Alterations in GCM1 expression or regulation may explain several aspects of two divergent severe placental insufficiency syndromes, namely preeclampsia and intrauterine growth restriction, which cause extreme preterm birth. Successful mammalian pregnancy demands two key steps in placental development, both of which are regulated by differentiation of the epithelial trophoblast lineage. 1 First, maternal blood flow to the implantation site must increase exponentially to serve the demands of the rapidly growing fetus. This is achieved through the invasion of extravillous cytotrophoblasts (EV-CTs) from the base of the placenta into the maternal uterine stroma, where they surround and dilate the distal portions of the utero-placental arteries. 2 Second, the increased delivery of maternal blood to the placenta must be matched by an exchanger organ to transfer nutrients, remove waste products and respiratory gases between the mother and the developing fetus. This requirement is achieved through the expansion and differentiation of the chorionic villous trees of the placenta. These villi are covered by a villous trophoblast compartment comprising of villous cytotrophoblasts (V-CTs) beneath a continuous multinucleated layer of syncytiotrophoblast (SCT), which is in direct contact with maternal blood. 3 In the human placenta, EV-CTs of the proximal portion of the anchoring villus cell column are proliferative, but more distal cells differentiate, as they invade and disperse into the uterine stroma. Here these cells surround and replace the smooth muscle cells of maternal uterine arteries, converting them into high-flow dilated sinusoids. The ar...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Glial cell missing-1 transcription factor is required for the differentiation of the human trophoblast

et al. 2009

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“…The expression of Gcm1 mRNA is visible in mouse chorion cells before the establishment of the contact with allantois [25]. In human, reduced expression of GCM1 gene analogue, is observed in pathologic condition called preeclampsia [26].…”

Section: Discussionmentioning

confidence: 99%

The Impact of 5-Azacytidine on Placental Weight, Glycoprotein Pattern and Proliferating Cell Nuclear Antigen Expression in Rat Placenta

et al. 2007

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“…and B.I., unpublished) and because altering GCM1 expression triggers parallel changes in human trophoblast cells (Baczyk et al, 2009) to those observed in mice. Interestingly, both increased and decreased GCM1 expression have been reported in human placenta obtained from complicated pregnancies (Chen et al, 2004;Fujito et al, 2006;McCaig and Lyall, 2009). The placental defects associated with either the loss or gain of Gcm1 function observed in mice (Anson-Cartwright et al, 2000) (this paper) provide a rationale for the apparently paradoxical findings of the aforementioned clinical studies.…”

Section: Research Articlementioning

confidence: 99%

p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

et al. 2011

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SUMMARYAbsence of the leucine zipper transcription factor p45NF-E2 results in thrombocytopenia, impaired placental vascularization and intrauterine growth restriction (IUGR) in mice. The mechanism underlying the p45NF-E2-dependent placental defect and IUGR remains unknown. Here, we show that the placental defect and IUGR of p45NF-E2 (Nfe2) null mouse embryos is unrelated to thrombocytopenia, establishing that embryonic platelets and platelet-released mediators are dispensable for placentation. Rather, p45NF-E2, which was hitherto thought to be specific to hematopoietic cells, is expressed in trophoblast cells, where it is required for normal syncytiotrophoblast formation, placental vascularization and embryonic growth. Expression of p45NF-E2 in labyrinthine trophoblast cells colocalizes with that of Gcm1, a transcription factor crucial for syncytiotrophoblast formation. In the absence of p45NF-E2, the width of syncytiotrophoblast layer 2 and the expression of Gcm1 and Gcm1-dependent genes (Synb and Cebpa) are increased. In vitro, p45NF-E2 deficiency results in spontaneous syncytiotrophoblast formation, which can be reversed by Gcm1 knockdown. Increased Gcm1 expression in the absence of p45NF-E2 is dependent on enhanced protein acetylation, including post-translational modification of Gcm1. Increasing and inhibiting acetylation in the placenta of wild-type control embryos phenocopies and corrects, respectively, the changes observed in p45NF-E2-deficient embryos. These studies identify a novel function of p45NF-E2 during placental development: in trophoblast cells, p45NF-E2 represses Gcm1 and syncytiotrophoblast formation via acetylation.

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Decreased Placental GCM1 (Glial Cells Missing) Gene Expression in Pre-eclampsia

Cited by 103 publications

References 25 publications

Glial cell missing-1 transcription factor is required for the differentiation of the human trophoblast

Glial cell missing-1 transcription factor is required for the differentiation of the human trophoblast

The Impact of 5-Azacytidine on Placental Weight, Glycoprotein Pattern and Proliferating Cell Nuclear Antigen Expression in Rat Placenta

p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

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