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

Baczyk, Dora; Drewlo, Sascha; Proctor, Leslie; Dunk, Caroline; Lye, Stephen J.; Kingdom, John

doi:10.1038/cdd.2009.1

Cited by 189 publications

(159 citation statements)

References 33 publications

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“…S2 ). It has been reported that upregulation of GCM1 , syncytin-1 and syncytin-2 are required for FK-induced fusion of BeWo cells 29,42 . We therefore examined whether β -catenin / BCL9L / TCF signalling is required for FK-induced fusion of BeWo cells.…”

Section: O C K S I C O N T R O L S I -C a T -1 M O C K S I C O N T mentioning

confidence: 99%

Identification of a link between Wnt/β-catenin signalling and the cell fusion pathway

et al. 2011

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Cell fusion has a critical role in various developmental processes, immune response, tissue homeostasis and regeneration, and possibly, in cancer. However, the signals that regulate cell fusion remain poorly understood. In a screen for novel targets of Wnt / β -catenin signalling, we identifi ed glial cells missing 1 ( GCM1 ), which encodes a transcription factor that is involved in epigenetic regulation and is critical for the fusion of syncytiotrophoblast (ST) cells. Here we show that β -catenin / BCL9-Like (BCL9L) / T-cell factor 4 (TCF4) signalling directly targets the GCM1 / syncytin pathway and thereby regulates the fusion of human choriocarcinoma cells. Furthermore, we show that the GCM1 / syncytin-B pathway is signifi cantly downregulated in the placenta of BCL9L-defi cient mice and that the fusion and differentiation of ST-II cells are blocked. Our results demonstrate a signal transduction pathway that regulates cell fusion, and may provide intriguing perspectives into the various biological and pathological processes that involve cell fusion.

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Section: O C K S I C O N T R O L S I -C a T -1 M O C K S I C O N T mentioning

confidence: 99%

Identification of a link between Wnt/β-catenin signalling and the cell fusion pathway

et al. 2011

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“…and B.I., unpublished) and because altering GCM1 expression triggers parallel changes in human trophoblast cells (Baczyk et al, 2009) to those observed in mice.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).…”

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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“…GCMa and GCMb are predominantly expressed in developing placenta and the parathyroid gland, respectively (5,16,29). GCMa instructs trophoblast stem cells to differentiate into syncytiotrophoblast cells (1,2). Abnormal development of placenta causes embryonic death in GCMa knockout mice (33).…”

Section: Introductionmentioning

confidence: 99%

PMA-induced GCMa phosphorylation stimulates its transcriptional activity and degradation

et al. 2012

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Glial cells missing Drosophila homolog a (GCMa) is a member of the GCM transcription factor family and plays critical roles in trophoblast differentiation and placental functions. It is well established that the cyclic AMP (cAMP)-dependent pathway induces the expression and transcriptional activity of GCMa by regulating post-translational modifications of GCMa, which results in enhancement of trophoblast differentiation. We previously observed that phorbol 12-myristate 13-acetate (PMA) stimulates phosphorylation of GCMa on serines 328, 378 and 383 through the protein kinase C (PKC)-and mitogen-activated protein kinase kinase (MEK)/extracellular signalregulated kinase (ERK)-dependent pathway, which decreases the protein stability of GCMa. Here we report that PMA increases the ubiquitination level of GCMa, dependent on the phosphorylation of GCMa on serines 328, 378 and 383. We found that this phosphorylation also stimulates the transcriptional activity of GCMa. Our data indicate that the PMA-induced PKC-and MEK/ERKdependent pathway enhances the degradation as well as the transcriptional activity of GCMa. We also examined the impact of this signaling pathway on trophoblasts and the results suggest that the PKC-and MEK/ERK-dependent pathway is involved in the regulation of trophoblast differentiation.

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

Cited by 189 publications

References 33 publications

Identification of a link between Wnt/β-catenin signalling and the cell fusion pathway

Identification of a link between Wnt/β-catenin signalling and the cell fusion pathway

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

PMA-induced GCMa phosphorylation stimulates its transcriptional activity and degradation

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