scholarly journals 016.Role of cited genes in placental morphogenesis: studies in null mutant mice

2004 ◽  
Vol 16 (9) ◽  
pp. 16
Author(s):  
S. L. Dunwoodie ◽  
S. L. Withington ◽  
D. B. Sparrow ◽  
A. N. Scott ◽  
J. I. Preis ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Giant Cells ◽  
Maternal Blood ◽  
Postnatal Period ◽  
Null Mutant ◽  
Placental Development ◽  
Null Mutant Mice ◽  
And Function ◽  
Trophoblast Giant Cells ◽  
Null Mutants

Cited1 and Cited2 interact with CBP and p300. CBP/p300 bind numerous proteins and evidence exists, for Cited2 at least, that Cited binding prevents the binding of other proteins to CBP/p300. Since CBP/p300 interact with many proteins, can acetylate protein and DNA, and act as a ubiquitin ligase, it is likely that Cited1 and Cited2 function at a number of sites during development. We have generated mice that carry a null mutant allele for each of these genes. Analysis of null mutant embryos demonstrates that both Cited1 and Cited2 are required for normal embryonic development and survival. Although both Cited1 and Cited2 are expressed in the developing embryo and placenta, it appears that abnormal placental development and function is the cause of embryonic death. The defect that develops in the placentas of Cited1 null mutants is not apparent until late in gestation (16.5dpc). Cited1 null mutants are smaller than controls at birth and die during the early postnatal period. The placentas of these mutants are disorganised, with spongiotrophoblasts projecting in to the labyrinthine layer. In addition, resin casts of the maternal blood spaces within these placentas revealed extremely enlarged blood sinuses. We are searching for factors that could result in the increased size of the maternal blood sinuses. Cited2 null placentas and embryos are significantly smaller than controls; mutants die 3/4 the way through gestation (15.5dpc). The null mutant placentas have proportionally fewer spongiotrophoblasts, trophoblast giant cells and invasive trophoblasts. In addition, resin casts of fetal vasculature of the placenta reveal that the capillary network is underdeveloped. Through the isolation of trophoblast stem (TS) cells we are exploring the possibility that TS cell proliferation and/or differentiation is impaired due to a lack of Cited2. We suspect that the development of the phenotype may relate to the Hypoxia Inducible Factor-1a (HIF1a) transcription factor as Cited2 expression is induced by HIF1 and it acts to negatively regulate its activity.

scholarly journals Mouse Model of Abortion Induced by Brucella abortus Infection

2012 ◽  
Vol 7 (3) ◽  
pp. 313-318
Author(s):  
Masahisa Watarai ◽  
Keyword(s):  
Bacterial Infection ◽  
Brucella Abortus ◽  
Bacterial Colonization ◽  
Giant Cells ◽  
Placental Development ◽  
Pregnant Mice ◽  
Ifn Γ ◽  
Bacterial Replication ◽  
And Function ◽  
Trophoblast Giant Cells

The mechanisms of abortion induced by bacterial infection are largely unknown. We found that Brucella abortus, a causative agent of brucellosis and a facultative intracellular pathogen, caused abortion in pregnant mice. High rates of abortion are observed for bacterial infection on day 4.5 of gestation, but not for other days. Regardless of whether fetuses are aborted or not, the transmission of bacteria to the fetus and bacterial replication in the placenta are observed. There is a higher degree of bacterial colonization in the placenta than in other organs and many bacteria are detected in trophoblast giant cells in the placenta. The intracellular growth-defective virB4 mutant and attenuated vaccine strain S19 do not induce abortion. In the case of abortion, the induction of IFN-γ and RANTES production is observed at day 7.5 of gestation – the placental development period – for infection by the wild type strain but not by the virB4 mutant or S19. B. abortus-infected pregnant IFN-γ knockoutmice die within 15 days of infection, but nonpregnant IFN-γ knockout mice remain alive. The neutralization of IFN-γ or RANTES, in which production is induced by infection with B. abortus serves to prevent abortion. These results indicate that abortion induced by B. abortus infection is regulated by IFN-γ during the period of placental development, and the production and function of RANTES are correlated with IFN-γ.

scholarly journals The transcriptional co-repressor TLE3 regulates development of trophoblast giant cells lining maternal blood spaces in the mouse placenta

2013 ◽  
Vol 382 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Malgorzata Gasperowicz ◽  
Cordula Surmann-Schmitt ◽  
Yoshio Hamada ◽  
Florian Otto ◽  
James C. Cross
Keyword(s):  
Giant Cells ◽  
Maternal Blood ◽  
Mouse Placenta ◽  
Trophoblast Giant Cells

Disruption of the mouse RBP-J kappa gene results in early embryonic death

Development ◽  
1995 ◽  
Vol 121 (10) ◽  
pp. 3291-3301 ◽  
Author(s):  
C. Oka ◽  
T. Nakano ◽  
A. Wakeham ◽  
J.L. de la Pompa ◽  
C. Mori ◽  
...  
Keyword(s):  
Es Cells ◽  
Marker Gene ◽  
Embryonic Stem ◽  
The Body ◽  
Mutant Mice ◽  
Null Mutant ◽  
Placental Development ◽  
Developmental Abnormalities ◽  
Null Mutant Mice ◽  
Severe Growth

The RBP-J kappa protein is a transcription factor that recognizes the sequence C(T)GTGGGGA. The RBP-J kappa gene is highly conserved in a wide variety of species and the Drosophila homologue has been shown to be identical to Suppressor of Hairless [Su(H)] which plays important roles in the development of the peripheral nervous system. To explore the function of the RBP-J kappa gene in mouse embryogenesis, a mutation was introduced into the functional RBP-J kappa gene in embryonic stem (ES) cells by homologous recombination. Null mutant ES cells survived but null mutant mice showed embryonic lethality before 10.5 days of gestation. The mutant mice showed severe growth retardation as early as 8.5 days of gestation. Developmental abnormalities, including incomplete turning of the body axis, microencephaly, abnormal placental development, anterior neuropore opening and defective somitogenesis, were observed in the mutant mice at 9.5 days of gestation. RBP-J kappa mutant embryos expressed a posterior mesodermal marker FGFR1. Their irregularly shaped somites expressed a somite marker gene Mox 1 but failed to express myogenin. The RBP-J kappa gene was revealed to be essential for postimplantation development of mice.

Desmosomal localization of beta-catenin in the skin of plakoglobin null-mutant mice

Development ◽  
1999 ◽  
Vol 126 (2) ◽  
pp. 371-381 ◽  
Author(s):  
C. Bierkamp ◽  
H. Schwarz ◽  
O. Huber ◽  
R. Kemler
Keyword(s):  
Heart Defects ◽  
Microscopic Analysis ◽  
Beta Catenin ◽  
Null Mutant ◽  
Electron Microscopic ◽  
Developmental Defects ◽  
Keratin Filaments ◽  
Embryonic Skin ◽  
Null Mutant Mice ◽  
And Function

Plakoglobin, a protein belonging to the Armadillo-repeat gene family, is the only component that adherens junctions and desmosomes have in common. Plakoglobin null-mutant mouse embryos die because of severe heart defects and may exhibit an additional skin phenotype, depending on the genetic background. Lack of plakoglobin affects the number and structure of desmosomes, resulting in visible defects when cells are subjected to increasing mechanical stress, e.g. when embryonic blood starts circulating or during skin differentiation. By analysing plakoglobin-negative embryonic skin differentiation in more detail, we show here that, in the absence of plakoglobin, its closest homologue, beta-catenin, becomes localized to desmosomes and associated with desmoglein. This substitution may account for the relatively late appearance of the developmental defects seen in plakoglobin null-mutant embryos. beta-catenin cannot, however, fully compensate a lack of plakoglobin. In the absence of plakoglobin, there was reduced cell-cell adhesion, resulting in large intercellular spaces between keratinocytes, subcorneal acantholysis and necrosis in the granular layer of the skin. Electron microscopic analysis documented a reduced number of desmosomes, and those present lacked the inner dense plaque and had fewer keratin filaments anchored. Our analysis underlines the central role of plakoglobin for desmosomal assembly and function during embryogenesis.

scholarly journals Psg22 expression in mouse trophoblast giant cells is associated with gene inversion and co-expression of antisense long non-coding RNAs

Reproduction ◽  
2015 ◽  
Vol 149 (1) ◽  
pp. 125-137 ◽  
Author(s):  
John M Williams ◽  
Melanie Ball ◽  
Andrew Ward ◽  
Tom Moore
Keyword(s):  
Late Pregnancy ◽  
Giant Cells ◽  
Maternal Blood ◽  
Protein Domain ◽  
Immunoglobulin Superfamily ◽  
Genomic Locus ◽  
Non Coding Rna ◽  
Domain Organisation ◽  
Trophoblast Giant Cells ◽  
Long Non Coding Rna

Pregnancy-specific glycoproteins (PSGs) are secreted carcinoembryonic antigen (CEA)-related cell adhesion molecules-related members of the immunoglobulin superfamily and are encoded by multigene families in species with haemochorial placentation. PSGs may be the most abundant trophoblast-derived proteins in human maternal blood in late pregnancy and there is evidence that dysregulation of PSG expression is associated with gestational pathology. PSGs are produced by syncytiotrophoblast in the human placenta and by trophoblast giant cells (TGCs) and spongiotrophoblast in rodents, and are implicated in immune regulation, angiogenesis and regulation of platelet function. PSGs are encoded by 17 genes in the mouse and ten genes in the human. While functions appear to be conserved, the typical protein domain organisation differs between species. We analysed the evolution of the mouse Psg genomic locus structure and report inversion of the Psg22 gene within the locus. Psg22 is the most abundant Psg transcript detected in the first half of mouse pregnancy and we identified antisense long non-coding RNA (lncRNA) transcripts adjacent to Psg22 associated with an active local chromatin conformation. This suggests that an epigenetic regulatory mechanism may underpin high Psg22 expression relative to the other Psg gene family members in TGCs.

scholarly journals Effect of Toxoplasma gondii Infection Kinetics on Trophoblast Cell Population in Calomys callosus, a Model of Congenital Toxoplasmosis

2002 ◽  
Vol 70 (12) ◽  
pp. 7089-7094 ◽  
Author(s):  
E. A. V. Ferro ◽  
D. A. O. Silva ◽  
E. Bevilacqua ◽  
J. R. Mineo
Keyword(s):  
Toxoplasma Gondii ◽  
Fetal Liver ◽  
Congenital Toxoplasmosis ◽  
Giant Cells ◽  
Maternal Blood ◽  
Cell Infection ◽  
Sequence Of Events ◽  
Calomys Callosus ◽  
Toxoplasma Gondii Infection ◽  
Trophoblast Giant Cells

ABSTRACT This work evaluated the kinetics of events that occur in the placenta of Calomys callosus after Toxoplasma gondii infection. Animals on the first day of pregnancy (dop) and virgin nonpregnant females were perorally infected with 20 cysts of T. gondii strain ME49. After 100 days of infection, the virgin animals were mated and received an additional 20 cysts on the first dop. The placentas and the embryos from both acutely and chronically infected animals were analyzed up to day 20 of pregnancy by morphological and immunocytochemical assays. Noninfected and infected animals exhibited placenta with normal morphology. From the seventh dop and infection onwards, liver and spleen cells of the infected animals contained several parasitophorous vacuoles. On the 13th day, the maternal blood present at the placental blood spaces contained T. gondii-infected leukocytes. Infected placental cells were only seen on the 15th dop, being the trophoblast giant cells, the first cell type to contain signs of the parasite internalization, followed by labyrinth zone cells 24 h later and spongiotrophoblast cells only after the 19th dop. Fetal liver and brain were infected by T. gondii concomitantly to the labyrinth cell infection. No signals of infection were observed on placentas and embryos from chronically infected animals. Therefore, considering the sequence of events leading to the infection of the various organs, it could be hypothesized that the placenta is infected later on during pregnancy, which may be related to the defense roles played by this structure. However, trophoblast giant cells are unable to completely stop the progression of T. gondii infection towards the fetal tissues. C. callosus was demonstrated to be a suitable experimental model to study the dynamics of congenital toxoplasmosis.

scholarly journals Placental but Not Heart Defects Are Associated with Elevated Hypoxia-Inducible Factor α Levels in Mice Lacking Prolyl Hydroxylase Domain Protein 2

2006 ◽  
Vol 26 (22) ◽  
pp. 8336-8346 ◽  
Author(s):  
Kotaro Takeda ◽  
Vivienne C. Ho ◽  
Hiromi Takeda ◽  
Li-Juan Duan ◽  
Andras Nagy ◽  
...  
Keyword(s):  
Heart Defects ◽  
Interventricular Septum ◽  
Hypoxia Inducible Factor ◽  
Giant Cells ◽  
Branching Morphogenesis ◽  
Mouse Development ◽  
Protein Levels ◽  
The Stability ◽  
Factor Α ◽  
Trophoblast Giant Cells

ABSTRACT PHD1, PHD2, and PHD3 are prolyl hydroxylase domain proteins that regulate the stability of hypoxia-inducible factor α subunits (HIF-α). To determine the roles of individual PHDs during mouse development, we disrupted all three Phd genes and found that Phd2 − / − embryos died between embryonic days 12.5 and 14.5 whereas Phd1 −/− or Phd3 −/− mice were apparently normal. In Phd2 − / − mice, severe placental and heart defects preceded embryonic death. Placental defects included significantly reduced labyrinthine branching morphogenesis, widespread penetration of the labyrinth by spongiotrophoblasts, and abnormal distribution of trophoblast giant cells. The expression of several trophoblast markers was also altered, including an increase in the spongiotrophoblast marker Mash2 and decreases in the labyrinthine markers Tfeb and Gcm1. In the heart, trabeculae were poorly developed, the myocardium was remarkably thinner, and interventricular septum was incompletely formed. Surprisingly, while there were significant global increases in HIF-α protein levels in the placenta and the embryo proper, there was no specific HIF-α increase in the heart. Taken together, these data indicate that among all three PHD proteins, PHD2 is uniquely essential during mouse embryogenesis.

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 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.

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