scholarly journals DYNAMIC REGULATION OF AP-1 TRANSCRIPTIONAL COMPLEXES DIRECTS TROPHOBLAST DIFFERENTIATION

2015 ◽  
pp. MCB.00118-15 ◽  
Author(s):  
Kaiyu Kubota ◽  
Lindsey N. Kent ◽  
M.A Karim Rumi ◽  
Katherine F. Roby ◽  
Michael J. Soares
Keyword(s):  
Transcriptome Profiling ◽  
Giant Cells ◽  
Trophoblast Cells ◽  
Placental Development ◽  
Dynamic Regulation ◽  
In Vivo Experiments ◽  
Lineage Differentiation ◽  
Transcriptional Complexes ◽  
Trophoblast Giant Cells

Placentation is a process that establishes the maternal-fetal interface and is required for successful pregnancy. The epithelial component of the placenta consists of trophoblast cells, which possess the capacity for multi-lineage differentiation and are responsible for placental-specific functions. FOS like antigen 1 (FOSL1), a component of AP-1 transcription factor complexes, contributes to the regulation of placental development. FOSL1 expression is restricted to trophoblast giant cells and invasive trophoblast cells. In the present study, we characterized the FOSL1 regulatory pathway in rat trophoblast cells. Transcriptome profiling in control and FOSL1 knockdown cells identified FOSL1 dependent gene sets linked to endocrine and invasive functions. FOSL1 was shown to occupy AP-1 binding sites within these gene loci, determined by chromatin immunoprecipitation (ChIP). Complementary in vivo experiments using trophoblast specific-lentiviral delivery of FOSL1 shRNAs provided an in vivo validation of FOSL1 targets. FOSL1 actions require a dimerization partner. Co-immunoprecipitation, co-immunolocalization, and ChIP analyses showed that FOSL1 interacts with JUNB and to a lesser extent JUN in differentiating trophoblast cells. Knockdown of FOSL1 and JUNB expression inhibited both endocrine and invasive properties of trophoblast cells. In summary, FOSL1 recruits JUNB to form AP-1 transcriptional complexes that specifically regulate the endocrine and invasive trophoblast phenotype.

scholarly journals Localization of paternal H-2K antigens on murine trophoblast cells in vivo.

1982 ◽  
Vol 155 (6) ◽  
pp. 1679-1689 ◽  
Author(s):  
S Chatterjee-Hasrouni ◽  
P K Lala
Keyword(s):  
Uterine Artery ◽  
Giant Cells ◽  
Capillary Endothelium ◽  
Trophoblast Cells ◽  
In Vivo Expression ◽  
Trophoblast Giant Cells ◽  
Negative Controls

We have previously shown the presence of H-2K and D antigens of both parental haplotypes on dispersed murine trophoblast cells. The question still remained whether such antigens are sequestered away from the sinusoidal face of these cells making them inert as allografts. The in vivo expression of H-2 antigens on these cells was therefore examined radioautographically after perfusion of 125I-labeled monoclonal and anti-H-2Kk (anti-paternal) antibody directly into individual placental branches of the uterine artery suppling 15-d-old (C57BL/6J female) X CBA/J male) placentae. Syngeneic C57BL/6J placentae served as negative controls. A radioautographic examination of 0.5-micrometer-thick sections revealed specific labeling of labyrinthine trophoblasts lining the sinusoids of allogeneic placentae. Most of this labeling was localized to the sinusoidal face of the cells as opposed to a weak labeling of the intracellular aspect. Spongiotrophoblasts and trophoblast giant cells did not label, but specific labeling of fetal capillary endothelium and some macrophages was also noted.

scholarly journals Phosphoinositide 3-Kinase (PI3K) Subunit p110δ Is Essential for Trophoblast Cell Differentiation and Placental Development in Mouse

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Xiwen Hu ◽  
Jiangchao Li ◽  
Qianqian Zhang ◽  
Lingyun Zheng ◽  
Guang Wang ◽  
...  
Keyword(s):  
Fetal Death ◽  
Underlying Mechanism ◽  
Giant Cells ◽  
Placental Development ◽  
Genetic Inactivation ◽  
Chorioallantoic Placenta ◽  
Phosphoinositide 3 Kinase ◽  
Trophoblast Giant Cells ◽  
Mammalian Embryonic Development

Abstract Maternal PI3K p110δ has been implicated in smaller litter sizes in mice, but its underlying mechanism remains unclear. The placenta is an indispensable chimeric organ that supports mammalian embryonic development. Using a mouse model of genetic inactivation of PI3K p110δ (p110δD910A/D910A), we show that fetuses carried by p110δD910A/D910A females were growth retarded and showed increased mortality in utero mainly during placentation. The placentas in p110δD910A/D910A females were anomalously anemic, exhibited thinner spongiotrophoblast layer and looser labyrinth zone, which indicate defective placental vasculogenesis. In addition, p110δ was detected in primary trophoblast giant cells (P-TGC) at early placentation. Maternal PI3K p110δ inactivation affected normal TGCs generation and expansion, impeded the branching of chorioallantoic placenta but enhanced the expression of matrix metalloproteinases (MMP-2, MMP-12). Poor vasculature support for the developing fetoplacental unit resulted in fetal death or gross growth retardation. These data, taken together, provide the first in vivo evidence that p110δ may play an important role in placental vascularization through manipulating trophoblast giant cell.

scholarly journals Phagocytosis as a potential mechanism for microbial defense of mouse placental trophoblast cells

Reproduction ◽  
2004 ◽  
Vol 128 (2) ◽  
pp. 207-218 ◽  
Author(s):  
A Amarante-Paffaro ◽  
G S Queiroz ◽  
S T Corrêa ◽  
B Spira ◽  
E Bevilacqua
Keyword(s):  
Giant Cells ◽  
Interferon Γ ◽  
Immune Defense ◽  
Trophoblast Cells ◽  
Histological Techniques ◽  
Complement Component C3 ◽  
Microbial Defense ◽  
Trophoblast Giant Cells

Trophoblast giant cells are active phagocytes during implantation and post-implantation. Phagocytosis decreases during placental maturation as the phagocytic function of nutrition is gradually replaced by the direct uptake of nutrients by the labyrinth zone trophoblast. We hypothesize that, after placental maturation, trophoblast cells maintain phagocytic functions for purposes other than nutrition. This study employs histological techniques to examine the ability of trophoblast cells to phagocytose microorganisms (yeast or bacteria)–in vivoin females receiving thioglycolate to activate macrophages andin vitroin the presence of phagocytic promoters such as interferon-γ and complement component C3. Placental trophoblast cells from the second half of gestation show basal phagocytosis that can be dramatically up-regulated by these promoters when microorganisms are inoculated into pregnant animals or introduced into culture systems. Stimulated trophoblast cells phagocytosed organisms more rapidly and in greater numbers than non-stimulated trophoblast exposed to the same numbers of organisms. Taken together, our results indicate that trophoblast cells do not lose their ability to phagocytose during the placentation process, which may imply that trophoblast cells participate in embryonic and fetal innate immune defense through elimination of microorganisms present at the maternal–fetal interface.

The mechanism of mouse egg-cylinder morphogenesis in vitro

Development ◽  
1981 ◽  
Vol 61 (1) ◽  
pp. 277-287
Author(s):  
A. J. Copp
Keyword(s):  
Giant Cell ◽  
Cell Formation ◽  
Cell Movement ◽  
Giant Cells ◽  
Cell Number ◽  
Dependent Change ◽  
Morphogenesis In Vitro ◽  
Trophoblast Giant Cells

The number of trophoblast giant cells in outgrowths of mouse blastocysts was determined before, during and after egg-cylinder formation in vitro. Giant-cell numbers rose initially but reached a plateau 12 h before the egg cylinder appeared. A secondary increase began 24 h after egg-cylinder formation. Blastocysts whose mural trophectoderm cells were removed before or shortly after attachment in vitro formed egg cylinders at the same time as intact blastocysts but their trophoblast outgrowths contained fewer giant cells at this time. The results support the idea that egg-cylinder formation in vitro is accompanied by a redirection of the polar to mural trophectoderm cell movement which characterizes blastocysts before implantation. The resumption of giant-cell number increase in trophoblast outgrowths after egg-cylinder formation may correspond to secondary giant-cell formation in vivo. It is suggested that a time-dependent change in the strength of trophoblast cell adhesion to the substratum occurs after blastocyst attachment in vitro which restricts the further entry of polar cells into the outgrowth and therefore results in egg-cylinder formation.

Insulinotropic nucleobindin-2/nesfatin-1 is dynamically expressed in the haemochorial mouse and human placenta

2018 ◽  
Vol 30 (3) ◽  
pp. 519 ◽  
Author(s):  
Crystalyn B. Legg-St Pierre ◽  
Martina Mackova ◽  
Ewa I. Miskiewicz ◽  
Denise G. Hemmings ◽  
Suraj Unniappan ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Hormone Secretion ◽  
Giant Cells ◽  
Nutrient Sensing ◽  
Trophoblast Cells ◽  
Chorionic Villi ◽  
Capillary Endothelial Cells ◽  
A Site ◽  
Trophoblast Giant Cells

The placenta is the physiological bridge between mother and fetus and has life-sustaining functions during pregnancy, including metabolic regulation, fetal protection and hormone secretion. Nucleobindin-2 (NUCB2) is a calcium- and DNA-binding protein and precursor of nesfatin-1, a signalling peptide with multiple functions, including regulation of energy homeostasis and glucose transport. These are also key functions of the placenta, yet NUCB2/nesfatin-1 expression has never been comprehensively studied in this organ. In the present study, mouse placental samples from Embryonic Day (E) 7.5 to E17.5 and human chorionic villi from the first and second trimester, as well as term pregnancy, were analysed for NUCB2/nesfatin-1 expression by immunohistochemistry with an antiserum that recognised both NUCB2 and nesfatin-1. From E7.5 to E9.5, NUCB2/nesfatin-1 was expressed in the ectoplacental cone, then parietal trophoblast giant cells and early spongiotrophoblast. At E10.5–12.5, NUCB2/nesfatin-1 expression became detectable in the developing labyrinth. From E12.5 and onwards, NUCB2/nesfatin-1 was expressed in the glycogen trophoblast cells, as well as highly expressed in syncytiotrophoblast, sinusoidal trophoblast giant cells and fetal capillary endothelial cells of the labyrinth. In all trimesters of human pregnancy, NUCB2/nesfatin-1 was highly expressed in syncytiotrophoblast. In addition, there was a significant increase in NUCB2 expression in human primary trophoblast cells induced to syncytialise. Thus, the haemochorial mammalian placenta is a novel source of NUCB2/nesfatin-1 and likely a site of its action, with potential roles in glucose homeostasis and/or nutrient sensing.

scholarly journals Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Aruna Marchetto ◽  
Shunya Ohmura ◽  
Martin F. Orth ◽  
Maximilian M. L. Knott ◽  
Maria V. Colombo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Ewing Sarcoma ◽  
Target Genes ◽  
Transcriptome Profiling ◽  
In Vivo Experiments ◽  
Ets Family ◽  
Pdx Models

AbstractEwing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcription factors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAA-microsatellites as enhancers.Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 – a physiological driver of proliferation of osteo-chondrogenic progenitors – by binding to an intronic GGAA-microsatellite, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments including 3D and PDX models, we discover that constitutively high SOX6 expression promotes elevated levels of oxidative stress that create a therapeutic vulnerability toward the oxidative stress-inducing drug Elesclomol.Collectively, our results exemplify how aberrant activation of a developmental transcription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy.

In vivo and in vitro development of mouse embryos homozygous for the embryonic lethal velvet coat (Ve) mutation

Development ◽  
1981 ◽  
Vol 66 (1) ◽  
pp. 43-55
Author(s):  
J. Rossant ◽  
K. M. Vijh
Keyword(s):  
Inner Cell Mass ◽  
Cell Mass ◽  
Giant Cells ◽  
Blastocyst Stage ◽  
Parietal Endoderm ◽  
Trophoblast Giant Cells ◽  
Vitro Development ◽  
Ectoplacental Cone

Embryos homozygous for the velvet coat mutation, Ve/Ve, were recognized at 6·5 days post coitum by the reduced size of the ectodermal portions of the egg cylinder and the loose, columnar nature of the overlying endoderm. Later in development ectoderm tissues were sometimes entirely absent. Abnormalities appeared in the ectoplacental cone at 8·5 days but trophoblast giant cells and parietal endoderm appeared unaffected. Homozygotes could not be unequivocally identified at 5·5 days nor at the blastocyst stage but were recognized in blastocyst outgrowths by poor development of the inner cell mass derivatives, It has previously been suggested that Ve may exert its action at the blastocyst stage by reducing the size of the inner cell mass, but no evidence for such a reduction was found. Most of the observations on Ve/Ve homozygotes are, however, consistent with the hypothesis that Ve exerts its action primarily on later primitive ectoderm development.

Metalloproteinases mediate extracellular matrix degradation by cells from mouse blastocyst outgrowths

Development ◽  
1992 ◽  
Vol 114 (2) ◽  
pp. 447-456 ◽  
Author(s):  
O. Behrendtsen ◽  
C.M. Alexander ◽  
Z. Werb
Keyword(s):  
Extracellular Matrix ◽  
Giant Cells ◽  
Matrix Degradation ◽  
Trophoblast Cells ◽  
Type Iv Collagenase ◽  
Type Iv ◽  
The Matrix ◽  
Remodeling Of Extracellular Matrix ◽  
Trophoblast Giant Cells ◽  
Blocking Antibodies

The maintenance and developmental remodeling of extracellular matrix is crucial to such processes as uterine implantation and the cell migratory events of morphogenesis. When mouse blastocysts are placed in culture they adhere to extracellular matrix, and trophoblast giant cells migrate out onto the matrix and degrade it. The secretion of functional proteinases by developing mouse embryos increases dramatically at the time of implantation. By zymography we identified the major secreted gelatin-degrading proteinase, also known as type IV collagenase, as one migrating at 92 × 10(3) Mr. Several casein-degrading proteinases were also secreted. The tissue inhibitor of metalloproteinases (TIMP) inhibited all of the embryo-derived proteinases detected by gelatin gel zymography, indicating that they are metalloproteinases, whereas TIMP did not inhibit all of the caseinases. Urokinase was also secreted. Addition of TIMP at 5–500 nM effectively inhibited the degradation of matrix by the trophoblast outgrowths. Blocking antibodies directed against 92 × 10(3) Mr gelatinase abolished matrix degradation by the trophoblast cells. These observations suggest that several metalloproteinases are regulated in early development and that 92 × 10(3) Mr gelatinase, in particular, has a rate-limiting function in degradation of the maternal extracellular matrix by trophoblast cells.

Response of preimplantation rat blastocysts in vitro to extracellular uterine luminal components, serum and hormones

1977 ◽  
Vol 25 (1) ◽  
pp. 265-277
Author(s):  
M.A. Surani
Keyword(s):  
Calf Serum ◽  
Giant Cells ◽  
Biologically Active ◽  
Foetal Calf Serum ◽  
Active Components ◽  
Rat Serum ◽  
Pregnant Females ◽  
Trophoblast Giant Cells

The influence of extracellular environmental factors on preimplantation rat blastocysts was tested by determining the number of embryos which escaped from their zonae pellucidae, followed by attachment and outgrowth of trophoblast giant cells, after 72 h in culture Uterine luminal ocmponents from individual females, or hormones, were included in Dulbecco's medium which contained 4 mg/ml bovine serum albumin. In about 20% of cases, uterine fluids were embryotonic. However, uterine fluids from day-5 pregnant females, the day of implantation in the rat, were more potent in these tests than uterine fluids obtained from ovariectomized females treated with progesterone alone. The potency of a mixture of the 2 fluids was also high. Uterine fluids obtained at 14 h after an injection of oestradiol and progesterone to the ovariectomized females, were also effective in these tests. Rat serum and foetal calf serum were effective too, but steroids or insulin alone in the medium had no detectable influence on embryos. Serum or uterine luminal proteins appear to be essential for maintaining the viability of the blastocysts and for inducing the responses observed here. In the uterine fluids, some proteins released into the lumen after treatment of females with oestradiol and progesterone appear to be the biologically active components. Differences in the responses of blastocysts in vitro are compared with those in vivo.

scholarly journals Differentiation of Trophoblast Giant Cells and Their Metabolic Functions Are Dependent on Peroxisome Proliferator-Activated Receptor β/δ

2006 ◽  
Vol 26 (8) ◽  
pp. 3266-3281 ◽  
Author(s):  
Karim Nadra ◽  
Silvia I. Anghel ◽  
Elisabeth Joye ◽  
Nguan Soon Tan ◽  
Sharmila Basu-Modak ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Giant Cell ◽  
Giant Cells ◽  
Peroxisome Proliferator ◽  
Phosphatidylinositol 3 Kinase ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolic Functions ◽  
Integrin Linked Kinase ◽  
Trophoblast Giant Cells

ABSTRACT Mutation of the nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) severely affects placenta development, leading to embryonic death at embryonic day 9.5 (E9.5) to E10.5 of most, but not all, PPARβ/δ-null mutant embryos. While very little is known at present about the pathway governed by PPARβ/δ in the developing placenta, this paper demonstrates that the main alteration of the placenta of PPARβ/δ-null embryos is found in the giant cell layer. PPARβ/δ activity is in fact essential for the differentiation of the Rcho-1 cells in giant cells, as shown by the severe inhibition of differentiation once PPARβ/δ is silenced. Conversely, exposure of Rcho-1 cells to a PPARβ/δ agonist triggers a massive differentiation via increased expression of 3-phosphoinositide-dependent kinase 1 and integrin-linked kinase and subsequent phosphorylation of Akt. The links between PPARβ/δ activity in giant cells and its role on Akt activity are further strengthened by the remarkable pattern of phospho-Akt expression in vivo at E9.5, specifically in the nucleus of the giant cells. In addition to this phosphatidylinositol 3-kinase/Akt main pathway, PPARβ/δ also induced giant cell differentiation via increased expression of I-mfa, an inhibitor of Mash-2 activity. Finally, giant cell differentiation at E9.5 is accompanied by a PPARβ/δ-dependent accumulation of lipid droplets and an increased expression of the adipose differentiation-related protein (also called adipophilin), which may participate to lipid metabolism and/or steroidogenesis. Altogether, this important role of PPARβ/δ in placenta development and giant cell differentiation should be considered when contemplating the potency of PPARβ/δ agonist as therapeutic agents of broad application.

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