A PKA-ezrin-connexin 43 signaling complex controls gap junction communication and thereby trophoblast cell fusion

Pidoux, Guillaume; Gerbaud, Pascale; Dompierre, Jim; Lygren, Birgitte; Solstad, Therese; Évain-Brion, Danièle; Taskén, Kjetil

doi:10.1242/jcs.149609

Cited by 66 publications

(111 citation statements)

References 61 publications

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“…The ST layer is a major site for numerous important placental functions, including nutrient and ion exchange and the synthesis of steroid and peptide hormones required for fetal development and growth (7,8). Here, we have used primary VCT and EVCT cells isolated from first-trimester placentae to determine the effect of NKX3.1 on in vitro differentiation as a fusion phenotype (ST) and as an invasive phenotype (EVCT), respectively, on NKX3.1 expression.…”

Section: Nkx31 and Trophoblast Differentiation In Primary Trophoblasmentioning

confidence: 99%

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An EG-VEGF-Dependent Decrease in Homeobox Gene NKX3.1 Contributes to Cytotrophoblast Dysfunction: A Possible Mechanism in Human Fetal Growth Restriction

Murthi¹,

Brouillet²,

Pratt³

et al. 2015

Mol Med

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Section: Nkx31 and Trophoblast Differentiation In Primary Trophoblasmentioning

confidence: 99%

“…The ST layer plays a key role throughout pregnancy. It is the site for several important placental functions, including nutrient and ion exchange and the synthesis of hormones required for fetal growth and development (7,8). Thus, a syncytium that functions efficiently requires both fusion and differentiation of cytotrophoblasts (CTB).…”

Section: Introductionmentioning

confidence: 99%

An EG-VEGF-Dependent Decrease in Homeobox Gene NKX3.1 Contributes to Cytotrophoblast Dysfunction: A Possible Mechanism in Human Fetal Growth Restriction

Murthi¹,

Brouillet²,

Pratt³

et al. 2015

Mol Med

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“…4 Its formation, function and continued renewal depends upon vCT fusion with existing synCT, where cellular competence for fusion is initiated by activation of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway. 5,6 PKA directs multiple pathways important in trophoblast fusion, including the expression of the transcription factor glial cell missing 1 (GCM1). 7,8 Coordination and propagation of the fusion signal is controlled via gap junctions, 9,10 cytoskeletal reorganization 11,12 and remodeling of intercellular adhesion complexes.…”

mentioning

confidence: 99%

ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion

et al. 2015

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Trophoblasts, placental cells of epithelial lineage, undergo extensive differentiation to form the cellular components of the placenta. Trophoblast progenitor cell differentiation into the multinucleated syncytiotrophoblast is a key developmental process required for placental function, where defects in syncytiotrophoblast formation and turnover associate with placental pathologies and link to poor pregnancy outcomes. The cellular and molecular processes governing syncytiotrophoblast formation are poorly understood, but require the activation of pathways that direct cell fusion. The protease, A Disintegrin and Metalloproteinase 12 (ADAM12), controls cell fusion in myoblasts and is highly expressed in the placenta localizing to multiple trophoblast populations. However, the importance of ADAM12 in regulating trophoblast fusion is unknown. Here, we describe a function for ADAM12 in regulating trophoblast fusion. Using two distinct trophoblast models of cell fusion, we show that ADAM12 is dynamically upregulated and is under the transcriptional control of protein kinase A. siRNA-directed loss of ADAM12 impedes spontaneous fusion of primary cytotrophoblasts, whereas overexpression of the secreted variant, ADAM12S, potentiates cell fusion in the Bewo trophoblast cell line. Mechanistically, both ectopic and endogenous levels of ADAM12 were shown to control trophoblast fusion through E-cadherin ectodomain shedding and remodeling of intercellular boundaries. This study describes a novel role for ADAM12 in placental development, specifically highlighting its importance in controlling the differentiation of villous cytotrophoblasts into multinucleated cellular structures. Moreover, this work identifies E-cadherin as a novel ADAM12 substrate, and highlights the significance that cell adhesion molecule ectodomain shedding has in normal development. Cell Death and Differentiation (2015) 22, 1970-1984 doi:10.1038/cdd.2015 published online 24 April 2015 In mammalian development, the placenta forms the mechanical and physiological link between maternal and fetal circulations. In rodents and higher order primates, including humans, this transfer is achieved through extensive uterine infiltration by fetal-derived cells of epithelial lineage called trophoblasts.1 Trophoblast differentiation is essential for optimal placental function, where the underlying molecular processes regulating specific functions of distinct trophoblast populations are strictly controlled. Defects in trophoblast differentiation associate with impaired placental function and directly impact fetal and maternal health. Within the placenta, progenitor trophoblasts (also called villous cytotrophoblasts; vCTs) overlie a well-defined basal lamina forming an organized, mitotically active epithelial layer. vCT differentiation into an overlying multinucleated structure called the syncytiotrophoblast (synCT) is a key event in placental development. 3 The synCT, composed of millions of nuclei sharing one common cytoplasm, directs nutrient and gas exchange between m...

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“…pCTB fusion was evaluated as described previously [25], with slight modification. Briefly, to visualize cell boundaries, plasma membrane protein desmoplakin was stained by immunofluorescence staining.…”

Section: Methodsmentioning

confidence: 99%

A Rho-associated coiled-coil containing kinases (ROCK) inhibitor, Y-27632, enhances adhesion, viability and differentiation of human term placenta-derived trophoblasts in vitro

et al. 2017

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Although human term placenta-derived primary cytotrophoblasts (pCTBs) represent a good human syncytiotrophoblast (STB) model, in vitro culture of pCTBs is not always easily accomplished. Y-27632, a specific inhibitor of Rho-associated coiled-coil containing kinases (ROCK), reportedly prevented apoptosis and improved cell-to-substrate adhesion and culture stability of dissociated cultured human embryonic stem cells and human corneal endothelial cells. The Rho kinase pathway regulates various kinds of cell behavior, some of which are involved in pCTB adhesion and differentiation. In this study, we examined Y-27632’s potential for enhancing pCTB adhesion, viability and differentiation. pCTBs were isolated from term, uncomplicated placentas by trypsin–DNase I–Dispase II treatment and purified by HLA class I-positive cell depletion. Purified pCTBs were cultured on uncoated plates in the presence of epidermal growth factor (10 ng/ml) and various concentrations of Y-27632. pCTB adhesion to the plates was evaluated by phase-contrast imaging, viability was measured by WST-8 assay, and differentiation was evaluated by immunofluorescence staining, expression of fusogenic genes and hCG-β production. Ras-related C3 botulinum toxin substrate 1 (Rac1; one of the effector proteins of the Rho family) and protein kinase A (PKA) involvement was evaluated by using their specific inhibitors, NSC-23766 and H-89. We found that Y-27632 treatment significantly enhanced pCTB adhesion to plates, viability, cell-to-cell fusion and hCG-β production, but showed no effects on pCTB proliferation or apoptosis. Furthermore, NSC-23766 and H-89 each blocked the effects of Y-27632, suggesting that Y-27632 significantly enhanced pCTB differentiation via Rac1 and PKA activation. Our findings suggest that Rac1 and PKA may be interactively involved in CTB differentiation, and addition of Y-27632 to cultures may be an effective method for creating a stable culture model for studying CTB and STB biology in vitro.

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A PKA-ezrin-connexin 43 signaling complex controls gap junction communication and thereby trophoblast cell fusion

Cited by 66 publications

References 61 publications

An EG-VEGF-Dependent Decrease in Homeobox Gene NKX3.1 Contributes to Cytotrophoblast Dysfunction: A Possible Mechanism in Human Fetal Growth Restriction

An EG-VEGF-Dependent Decrease in Homeobox Gene NKX3.1 Contributes to Cytotrophoblast Dysfunction: A Possible Mechanism in Human Fetal Growth Restriction

ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion

A Rho-associated coiled-coil containing kinases (ROCK) inhibitor, Y-27632, enhances adhesion, viability and differentiation of human term placenta-derived trophoblasts in vitro

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