Syncytial fusion of human trophoblast depends on caspase 8

Black, Shawn C.; Kadyrov, Mamed; Kaufmann, Peter; Ugele, Bernhard; Emans, Neil; Huppertz, Berthold

doi:10.1038/sj.cdd.4401307

Cited by 160 publications

(86 citation statements)

References 56 publications

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“…Inhibition of the caspase 8 expression in human placental explants inhibits the progression of the apoptosis cascade and, thus, syncytial fusion. 30 Therefore, a controlled rate of apoptosis in the trophoblast layer is essential; imbalance in trophoblast turnover may lead to insufficient villi formation or degeneration of SCT.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorothioate oligonucleotides and controls were designed and manufactured by Biognostik (Gottingen, Germany) (sequence in Table 2). Floating villous and extravillous explants were incubated in the presence of either 1 mM antisense oligonucleotides, sense oligonucleotides control, 100 nM siRNA or non-silencing siRNA control (n ¼ 9) (as described in Black et al 30 ). Nontreated controls showed no significant difference compared with the non-silencing control (data not shown).…”

Section: First Trimester Villous Explant Culturesmentioning

confidence: 99%

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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%

Section: First Trimester Villous Explant Culturesmentioning

confidence: 99%

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

et al. 2009

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“…72 Using antisense oligonucleotides and caspase inhibitors, it was shown that activation of caspase-8 is essential during differentiation of human placental villous trophoblasts. 74 Another report established a role for caspase-3 in skeletal muscle differentiation: primary myoblasts from caspase-3 knockout mice displayed a severe lack of myotube and myofiber formation and a reduced expression of musclespecific genes. 75 Furthermore, the authors identified the serine/threonine Mammalian Sterile Twenty-like kinase (MST1) as a crucial effector of caspase-3, since a proteolytic fragment of MST1 rescued the differentiation defect of caspase-3 deficient myoblasts.…”

Section: Caspases In Cell Differentiationmentioning

confidence: 99%

“…Not determined Caspase- 8 Proliferation of T, B and NK cells 14,39,40 NF-kB activation following TcR-, TNF-, TLR-4-and Apo2/TRAIL-stimulation 5,12,16 dsRNA-induced NF-kB activation via its prodomain 25,26 Differentiation of monocytes into macrophages 72,73 Differentiation of placental villous trophoblasts 74 Caspase-9 Not determined Caspase-10 dsRNA-induced NF-kB activation via its prodomain 25,26 Caspase-11 Maturation of pro-inflammatory cytokines 102 Caspase-12 Attenuation of inflammation and susceptibility to sepsis 94,95 Caspase-14 Terminal differentiation of keratinocytes? 70,103 11 With the notable exception of DREDD, RNAi-mediated knockdown of the other fly caspases did not affect Relish processing in cells.…”

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confidence: 99%

Caspases in cell survival, proliferation and differentiation

et al. 2006

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Caspases, a family of evolutionarily, conserved cysteinyl proteases, mediate both apoptosis and inflammation through aspartate-specific cleavage of a wide number of cellular substrates. Most substrates of apoptotic caspases have been conotated with cellular dismantling, while inflammatory caspases mediate the proteolytic activation of inflammatory cytokines. Through detailed functional analysis of conditional caspase-deficient mice or derived cells, caspase biology has been extended to cellular responses such as cell differentiation, proliferation and NF-jB activation. Here, we discuss recent data indicating that nonapoptotic functions of caspases involve proteolysis exerted by their catalytic domains as well as non-proteolytic functions exerted by their prodomains. Homotypic oligomerization motifs in the latter mediate the recruitment of adaptors and effectors that modulate NF-jB activation. The non-apoptotic functions of caspases suggest that they may become activated independently of -or without -inducing an apoptotic cascade. Moreover, the existence of non-catalytic caspase-like molecules such as human caspase-12, c-FLIP and CARD-only proteins further supports the non-proteolytic functions of caspases in the regulation of cell survival, proliferation, differentiation and inflammation. Cell Death and Differentiation (2007) 14, 44-55. doi:10.1038/sj.cdd.4402047; published online 20 October 2006 Caspases are an evolutionarily conserved family of aspartatespecific cystein-dependent proteases with central functions in apoptotic and inflammatory signalling pathways.1 Certain caspases have large prodomains that contain related homotypic oligomerization motifs such as the caspase recruitment domain (CARD,

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“…26 Notably, caspase-8 has also been implicated in the differentiation of the human placental trophoblast, by mediating the syncytial fusion of the cytotrophoblast that accounts for the generation of the syncytiotrophoblast. 27 Loss-of-function mutations in the human caspase-8 gene cause defects in the activation of T, B and NK cells, culminating in immunodeficiency. 28 Similarly, knockout of caspase-8 (or that of its cytosolic adaptor FADD, i.e.…”

Section: Vital Functions Of Mammalian Caspasesmentioning

confidence: 99%

No death without life: vital functions of apoptotic effectors

et al. 2008

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As a result of the genetic experiments performed in Caenorhabditis elegans, it has been tacitly assumed that the core proteins of the 'apoptotic machinery' (CED-3, -4, -9 and EGL-1) would be solely involved in cell death regulation/execution and would not exert any functions outside of the cell death realm. However, multiple studies indicate that the mammalian orthologs of these C. elegans proteins (i.e. caspases, Apaf-1 and multidomain proteins of the Bcl-2 family) participate in cell death-unrelated processes. Similarly, loss-of-function mutations of ced-4 compromise the mitotic arrest of DNA-damaged germline cells from adult nematodes, even in a context in which the apoptotic machinery is inoperative (for instance due to mutations of egl-1 or ced-3). Moreover, EGL-1 is required for the activation of autophagy in starved nematodes. Finally, the depletion of caspaseindependent death effectors, such as apoptosis-inducing factor (AIF) and endonuclease G, provokes cell death-independent consequences, both in mammals and in yeast (Saccharomyces cerevisiae). These results corroborate the conjecture that any kind of protein that has previously been specifically implicated in apoptosis might have a phylogenetically conserved apoptosisunrelated function, most likely as part of an adaptive response to cellular stress.

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Syncytial fusion of human trophoblast depends on caspase 8

Cited by 160 publications

References 56 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

Caspases in cell survival, proliferation and differentiation

No death without life: vital functions of apoptotic effectors

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