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 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.

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.

Identification of two new nonclassical members of the rat prolactin family

2000 ◽  
Vol 24 (1) ◽  
pp. 95-108 ◽  
Author(s):  
N Sahgal ◽  
GT Knipp ◽  
B Liu ◽  
BM Chapman ◽  
G Dai ◽  
...  
Keyword(s):  
Giant Cell ◽  
Cell Layer ◽  
Giant Cells ◽  
Trophoblast Giant Cell ◽  
Related Protein ◽  
Junctional Zone ◽  
Dbest Database ◽  
Chorioallantoic Placenta ◽  
Trophoblast Giant Cells ◽  
Ectoplacental Cone

The prolactin (PRL) family is comprised of a group of hormones/cytokines that are expressed in the anterior pituitary, uterus, and placenta. These proteins participate in the control of maternal and fetal adaptations to pregnancy. In this report, we have identified two new nonclassical members of the rat PRL family through a search of the National Center for Biotechnology Information dbEST database. The cDNAs were sequenced and their corresponding mRNAs characterized. Overall, the rat cDNAs showed considerable structural similarities with mouse proliferin-related protein (PLF-RP) and prolactin-like protein-F (PLP-F), consistent with their classification as rat homologs for PLF-RP and PLP-F. The expression of both cytokines/hormones was restricted to the placenta. The intraplacental sites of PLF-RP and PLP-F synthesis differed in the rat and the mouse. In the mouse, PLF-RP was expressed in the trophoblast giant cell layer of the midgestation chorioallantoic and choriovitelline placentas and, during later gestation, in the trophoblast giant cell and spongiotrophoblast layers within the junctional zone of the mouse chorioallantoic placenta. In contrast, in the rat, PLF-RP was first expressed in the primordium of the chorioallantoic placenta (ectoplacental cone region) and, later, exclusively within the labyrinth zone of the chorioallantoic placenta. In the mouse, PLP-F is an exclusive product of the spongiotrophoblast layer, whereas in the rat, trophoblast giant cells were found to be the major source of PLP-F, with a lesser contribution from spongiotrophoblast cells late in gestation. In summary, we have established the presence of PLF-RP and PLP-F in the rat.

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.

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.

scholarly journals GATA-2 and GATA-3 regulate trophoblast-specific gene expression in vivo

Development ◽  
1997 ◽  
Vol 124 (4) ◽  
pp. 907-914 ◽  
Author(s):  
G.T. Ma ◽  
M.E. Roth ◽  
J.C. Groskopf ◽  
F.Y. Tsai ◽  
S.H. Orkin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Giant Cells ◽  
Placental Lactogen ◽  
Specific Gene ◽  
Wild Type ◽  
Specific Gene Expression ◽  
Decidual Tissue ◽  
Trophoblast Giant Cells ◽  
I Gene

We previously demonstrated that the zinc finger transcription factors GATA-2 and GATA-3 are expressed in trophoblast giant cells and that they regulate transcription from the mouse placental lactogen I gene promoter in a transfected trophoblast cell line. We present evidence here that both of these factors regulate transcription of the placental lactogen I gene, as well as the related proliferin gene, in trophoblast giant cells in vivo. Placentas lacking GATA-3 accumulate placental lactogen I and proliferin mRNAs to a level 50% below that reached in the wild-type placenta. Mutation of the GATA-2 gene had a similar effect on placental lactogen I expression, but led to a markedly greater reduction (5- to 6-fold) in proliferin gene expression. Placentas lacking GATA-2 secrete significantly less angiogenic activity than wild-type placentas as measured in an endothelial cell migration assay, consistent with a reduction in expression of the angiogenic hormone proliferin. Furthermore, within the same uterus the decidual tissue adjacent to mutant placentas displays markedly reduced neovascularization compared to the decidual tissue next to wild-type placentas. These results indicate that GATA-2 and GATA-3 are important in vivo regulators of trophoblast-specific gene expression and placental function, and reveal a difference in the effect of these two factors in regulating the synthesis of related placental hormones.

scholarly journals Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses

2000 ◽  
Vol 14 (24) ◽  
pp. 3191-3203
Author(s):  
David M. Adelman ◽  
Marina Gertsenstein ◽  
Andras Nagy ◽  
M. Celeste Simon ◽  
Emin Maltepe
Keyword(s):  
Cell Fate ◽  
Es Cells ◽  
Hypoxia Inducible Factor ◽  
Embryonic Stem ◽  
Giant Cells ◽  
Cell Fate Determination ◽  
Placental Development ◽  
Fate Determination

Placental development is profoundly influenced by oxygen (O2) tension. Human cytotrophoblasts proliferate in vitro under low O2 conditions but differentiate at higher O2 levels, mimicking the developmental transition they undergo as they invade the placental bed to establish the maternal–fetal circulation in vivo. Hypoxia-inducible factor-1 (HIF-1), consisting of HIF-1α and ARNT subunits, activates many genes involved in the cellular and organismal response to O2deprivation. Analysis of Arnt−/− placentas reveals an aberrant cellular architecture due to altered cell fate determination of Arnt−/− trophoblasts. Specifically, Arnt−/− placentas show greatly reduced labyrinthine and spongiotrophoblast layers, and increased numbers of giant cells. We further show that hypoxia promotes the in vitro differentiation of trophoblast stem cells into spongiotrophoblasts as opposed to giant cells. Our results clearly establish that O2 levels regulate cell fate determination in vivo and that HIF is essential for mammalian placentation. The unique placental phenotype of Arnt−/− animals also provides an important tool for studying the disease of preeclampsia. Interestingly, aggregation of Arnt−/− embryonic stem (ES) cells with tetraploid wild-type embryos rescues their placental defects; however, these embryos still die from yolk sac vascular and cardiac defects.

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.

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