ZO-1 is involved in trophoblastic cell differentiation in human placenta

Pidoux, Guillaume; Gerbaud, Pascale; Gnidehou, Sédami; Grynberg, Michaël; Geneau, Graziello; Gadrey, Jean; Carette, Diane; Cronier, Laurent; Évain-Brion, Danièle; Malassiné, André; Frendo, Jean-Louis

doi:10.1152/ajpcell.00484.2008

Cited by 67 publications

(47 citation statements)

References 52 publications

(60 reference statements)

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“…The nuclei were counterstained with DAPI, and immunostaining was analyzed using a laser-scanning microscope. To quantify syncytialization in BeWo cells and CTBs without bias, we performed a syncytium formation analysis as described previously (22). Briefly, three different non-overlapping fields were selected randomly for each time point under the microscope.…”

Section: Methodsmentioning

confidence: 99%

Glioma-associated Oncogene 2 Is Essential for Trophoblastic Fusion by Forming a Transcriptional Complex with Glial Cell Missing-a

Tang¹,

Tang²,

Wu³

et al. 2016

Journal of Biological Chemistry

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Cell-cell fusion of human villous trophoblasts, referred to as a process of syncytialization, acts as a prerequisite for the proper development and functional maintenance of the human placenta. Given the fact that the main components of the Hedgehog signaling pathway are expressed predominantly in the syncytial layer of human placental villi, in this study, we investigated the potential roles and underlying mechanisms of Hedgehog signaling in trophoblastic fusion. Activation of Hedgehog signaling by a variety of approaches robustly induced cell fusion and the expression of syncytial markers, whereas suppression of Hedgehog signaling significantly attenuated cell fusion and the expression of syncytial markers in both human primary cytotrophoblasts and trophoblast-like BeWo cells. Moreover, among glioma-associated oncogene (GLI) family transcriptional factors in Hedgehog signaling, knockdown of GLI2 but not GLI1 and GLI3 significantly attenuated Hedgehog-induced cell fusion, whereas overexpression of the GLI2 activator alone was sufficient to induce cell fusion. Finally, GLI2 not only stabilized glial cell missing-a, a pivotal transcriptional factor for trophoblastic syncytialization, but also formed a transcriptional heterodimer with glial cell missing-a to transactivate syncytin-1, a trophoblastic fusogen, and promote trophoblastic syncytialization. Taken together, this study uncovered a so far uncharacterized role of Hedgehog/GLI2 signaling in trophoblastic fusion, implicating that Hedgehog signaling, through GLI2, could be required for human placental development and pregnancy maintenance.

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Section: Methodsmentioning

confidence: 99%

Glioma-associated Oncogene 2 Is Essential for Trophoblastic Fusion by Forming a Transcriptional Complex with Glial Cell Missing-a

Tang¹,

Tang²,

Wu³

et al. 2016

Journal of Biological Chemistry

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“…1A). After a 72-h culture, the number of mononuclear cells and syncytia and the number of nuclei in syncytia were counted, and the fusion index (N Ϫ S)/T was determined (N is nuclei number in syncytia, S is number of syncytia, and T is total number of nuclei) (32). For each group of term, the experiment was performed with three different primary cultures obtained from three different placentas and run in duplicate each time.…”

Section: Methodsmentioning

confidence: 99%

Comparative expression of hCG β-genes in human trophoblast from early and late first-trimester placentas

Cocquebert

Berndt

Segond

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Human chorionic gonadotropin (hCG) displays a major role in pregnancy initiation and progression and is involved in trophoblast differentiation and fusion. However, the site and the type of dimeric hCG production during the first trimester of pregnancy is poorly known. At that time, trophoblastic plugs present in the uterine arteries disappear, allowing unrestricted flow of maternal blood to the intervillous space. The consequence is an important modification of the trophoblast environment, including a rise of oxygen levels from about 2.5% before 10 wk of amenorrhea (WA) to ∼8% after 12 WA. Two specific β-hCG proteins that differ from three amino acids have been described: type 1 (CGB7) and type 2 (CGB3, -5, and -8). Here, we demonstrated in situ and ex vivo on placental villi and in vitro in primary cultures of human cytotrophoblasts that type 1 and 2 β-hCG RNAs and proteins were expressed by trophoblasts and that these expressions were higher before blood enters in the intervillous space (8–9 vs. 12–14 WA). hCG was immunodetected in villous mononucleated cytotrophoblasts (VCT) and syncytiotrophoblast (ST) at 8–9 WA but only in ST at 12–14 WA. Furthermore, hCG secretion was fourfold higher in VCT cultures from 8–9 WA compared with 12–14 WA. Interestingly, VCT from 8–9 WA placentas were found to exhibit more fusion features. Taken together, we showed that type 1 and type 2 β-hCG are highly expressed by VCT in the early first trimester, contributing to the high levels of hCG found in maternal serum at this term.

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“…The other family of fusogens includes EFF1 and AFF1, which have been discovered in C. elegans (Mohler et al 2002, del Campo et al 2005, Sapir et al 2007). In addition to the above-mentioned fusogens, the expression of connexin 43, a hexamer from which gap junctions are comprised, is increased during the differentiation of CTB cells (Dunk et al 2012), while the expression of zona occludens-1, an adherens junction protein that 'zips' cells together, is predominantly present during CTB cells aggregation but is significantly decreased upon cell fusion (Pidoux et al 2010). Calponin 3 (CNN3), a CNN family member, is also a negative regulator of trophoblast fusion (Shibukawa et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Involvement of nephrin in human placental trophoblast syncytialization

Li¹,

Zheng²,

Wang³

et al. 2015

Reproduction

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The placenta has numerous functions, such as transporting oxygen and nutrients and building the immune tolerance of the fetus. Cell fusion is an essential process for placental development and maturation. In human placental development, mononucleated cytotrophoblast (CTB) cells can fuse to form a multinucleated syncytiotrophoblast (STB), which is the outermost layer of the placenta. Nephrin is a transmembrane protein that belongs to the Ig superfamily. Previous studies have shown that nephrin contributes to the fusion of myoblasts into myotubes in zebrafish and mice, presenting a functional conservation with its Drosophila ortholog sticks and stones. However, whether nephrin is involved in trophoblast syncytialization remains unclear. In this study, we report that nephrin was localized predominantly in the CTB cells and STB of human placenta villi from first trimester to term pregnancy. Using a spontaneous fusion model of primary CTB cells, the expression of nephrin was found to be increased during trophoblast cell fusion. Moreover, the spontaneous syncytialization and the expression of syncytin 2, connexin 43, and human chorionic gonadotropin beta were significantly inhibited by nephrin-specific siRNAs. The above results demonstrate that nephrin plays an important role in trophoblast syncytialization.

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ZO-1 is involved in trophoblastic cell differentiation in human placenta

Cited by 67 publications

References 52 publications

Glioma-associated Oncogene 2 Is Essential for Trophoblastic Fusion by Forming a Transcriptional Complex with Glial Cell Missing-a

Glioma-associated Oncogene 2 Is Essential for Trophoblastic Fusion by Forming a Transcriptional Complex with Glial Cell Missing-a

Comparative expression of hCG β-genes in human trophoblast from early and late first-trimester placentas

Involvement of nephrin in human placental trophoblast syncytialization

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