Mrj encodes a DnaJ-related co-chaperone that is essential for murine placental development

Development ◽  
1999 ◽  
Vol 126 (6) ◽  
pp. 1247-1258 ◽  
Author(s):  
P.J. Hunter ◽  
B.J. Swanson ◽  
M.A. Haendel ◽  
G.E. Lyons ◽  
J.C. Cross
Keyword(s):  
Protein Function ◽  
Cell Types ◽  
Giant Cells ◽  
Gene Trap ◽  
Developmental Defect ◽  
Placental Development ◽  
E Coli ◽  
Mouse Tissues ◽  
Transcription Factor Genes ◽  
Trophoblast Giant Cells

We have identified a novel gene in a gene trap screen that encodes a protein related to the DnaJ co-chaperone in E. coli. The gene, named Mrj (mammalian relative of DnaJ) was expressed throughout development in both the embryo and placenta. Within the placenta, expression was particularly high in trophoblast giant cells but moderate levels were also observed in trophoblast cells of the chorion at embryonic day 8.5, and later in the labyrinth which arises from the attachment of the chorion to the allantois (a process called chorioallantoic fusion). Insertion of the ROSAbetageo gene trap vector into the Mrj gene created a null allele. Homozygous Mrj mutants died at mid-gestation due to a failure of chorioallantoic fusion at embryonic day 8.5, which precluded formation of the mature placenta. At embryonic day 8.5, the chorion in mutants was morphologically normal and expressed the cell adhesion molecule beta4 integrin that is known to be required for chorioallantoic fusion. However, expression of the chorionic trophoblast-specific transcription factor genes Err2 and Gcm1 was significantly reduced. The mutants showed no abnormal phenotypes in other trophoblast cell types or in the embryo proper. This study indicates a previously unsuspected role for chaperone proteins in placental development and represents the first genetic analysis of DnaJ-related protein function in higher eukaryotes. Based on a survey of EST databases representing different mouse tissues and embryonic stages, there are 40 or more DnaJ-related genes in mammals. In addition to Mrj, at least two of these genes are also expressed in the developing mouse placenta. The specificity of the developmental defect in Mrj mutants suggests that each of these genes may have unique tissue and cellular activities.

scholarly journals A molecular mechanism of mouse placental spongiotrophoblast differentiation regulated by prolyl oligopeptidase

Zygote ◽  
2019 ◽  
Vol 27 (1) ◽  
pp. 49-53
Author(s):  
Yuki Maruyama ◽  
Atsushi P. Kimura
Keyword(s):  
Molecular Mechanism ◽  
Critical Role ◽  
Specific Inhibitor ◽  
Cell Types ◽  
Giant Cells ◽  
Akt Pathway ◽  
Prolyl Oligopeptidase ◽  
Trophoblast Stem ◽  
Trophoblast Stem Cell ◽  
Trophoblast Giant Cells

SummaryIn eutherian mammals, the placenta plays a critical role in embryo development by supplying nutrients and hormones and mediating interaction with the mother. To establish the fine connection between mother and embryo, the placenta needs to be formed normally, but the mechanism of placental differentiation is not fully understood. We previously revealed that mouse prolyl oligopeptidase (POP) plays a role in trophoblast stem cell (TSC) differentiation into two placental cell types, spongiotrophoblasts (SpT) and trophoblast giant cells. Here, we focused on SpT differentiation and attempted to elucidate a molecular mechanism. ForAscl2,Arnt, andEgfrgenes that are indispensable for SpT formation, we found that a POP-specific inhibitor, SUAM-14746, significantly decreasedAscl2expression, which was consistent with a significant decrease in expression ofFlt1, a gene downstream ofAscl2. Although this downregulation was unlikely to be mediated by the PI3K-Akt pathway, our results indicated that POP controls TSC differentiation into SpT by regulating theAscl2gene.

scholarly journals Reciprocal expression of 17α-hydroxylase-C17,20-lyase and aromatase cytochrome P450 during bovine trophoblast differentiation: a two-cell system drives placental oestrogen synthesis

Reproduction ◽  
2006 ◽  
Vol 131 (4) ◽  
pp. 669-679 ◽  
Author(s):  
G Schuler ◽  
G R Özalp ◽  
B Hoffmann ◽  
N Harada ◽  
P Browne ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Cell Types ◽  
Staining Intensity ◽  
Giant Cells ◽  
Cell System ◽  
Cellular Level ◽  
Specific Staining ◽  
Cytoplasmic Staining ◽  
Distinct Cell ◽  
Trophoblast Giant Cells

No definitive information is yet available on the steroidogenic capacity of the two morphologically distinct cell types forming the bovine trophoblast, the uninucleated trophoblast cells (UTCs) and the trophoblast giant cells (TGCs). Hence, in order to localise 17α-hydroxylase-C17,20-lyase (P450c17) on a cellular level and to monitor its expression as a function of gestational age, placentomes from pregnant (days 80–284; n = 19), prepartal (days 273–282; 24–36 h prior to the onset of labour; n = 3) and parturient cows (n = 5) were immunostained for P450c17 using an antiserum against the recombinant bovine enzyme. At all stages investigated, P450c17 was exclusively found in the UTCs of chorionic villi (CV), where staining was ubiquitous between days 80 and 160, but was largely restricted to primary CV and the branching sites of secondary CV between days 160 and 240. Thereafter, a distinct ubiquitous staining reoccurred in the UTCs of all CV in late pregnant, prepartal and parturient animals. Using an antiserum against human aromatase cytochrome P450 (P450arom), specific cytoplasmic staining was observed in TGCs. In placentomes from pregnant cows, staining intensity was higher in mature compared with immature TGCs and was more pronounced in the trophoblast covering big stem villi compared with the trophoblast at other sites of the villous tree. In placentomes of a parturient cow, specific staining was only found in mature TGCs that survived the normal, but substantial, prepartal decline in TGC numbers. These results clearly showed that bovine UTCs and TGCs exhibit different steroidogenic capacities, constituting a ‘two-cell’ organisation for oestrogen synthesis. P450c17 expression appears to be quickly down-regulated and P450arom is up-regulated when UTCs enter the TGC differentiation pathway.

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 Developmental expression of the homeobox protein Distal-less 3 and its relationship to progesterone production in mouse placenta

2005 ◽  
Vol 186 (2) ◽  
pp. 315-323 ◽  
Author(s):  
K A Berghorn ◽  
P A Clark ◽  
B Encarnacion ◽  
C J DeRegis ◽  
J K Folger ◽  
...  
Keyword(s):  
Giant Cells ◽  
Late Gestation ◽  
Developmental Expression ◽  
Placental Development ◽  
Progesterone Production ◽  
Mouse Placenta ◽  
Homeobox Protein ◽  
Trophoblast Stem Cell ◽  
Trophoblast Giant Cells

Distal-less 3 (Dlx3) is a homeobox factor that functions as a placental-specific transcriptional regulator. Dlx3 null mice (−/−) have compromised placental development and do not survive in utero past embryonic day (E) 9.5. The current studies were undertaken to examine the expression of Dlx3 in mouse placenta during gestation, and to determine whether Dlx3 was involved in placental progesterone production. Dlx3 was not detectable at E8.5 but was detected in E9.5 placenta with continuing but diminished expression through E15.5. Dlx3 immuno-localization was restricted to the labyrinth, was nuclear and was found in cytokeratin-positive cells. Previous studies in choriocarcinoma cell lines support the conclusion that Dlx3 is required for expression of 3′-hydroxysteroid dehydrogenase VI (3βHSD VI), an obligate enzyme in the production of progesterone by trophoblast giant cells. In a rat trophoblast stem cell line (Rcho-1), Dlx3 expression was non-detectable in Rcho-1 cells induced to differ-entiate using mitogen withdrawal. In vitro progesterone production in placental cultures and 3βHSD VI mRNA from Dlx3 (+/+), (+/−) and (−/−) mice were equivalent. In situ hybridization for 3βHSD VI revealed mRNA expression restricted to trophoblast giants cells with no detectable expression in the labyrinth suggesting that Dlx3 and 3βHSD VI were not colocalized within the placenta. These studies support the conclusion that Dlx3 protein expression is restricted to the labyrinth region of the murine placenta into late gestation and that Dlx3 does not appear to be expressed in trophoblast giant cells. Further, loss of Dlx3 was not correlated with synthesis of progesterone from E9.5 mouse placentas.

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 Morphological Characterization of Basally Located Uninucleate Trophoblast Cells as Precursors of Bovine Binucleate Trophoblast Giant Cells

2018 ◽  
Vol 205 (3) ◽  
pp. 151-163 ◽  
Author(s):  
Jeannette Attiger ◽  
Alois Boos ◽  
Karl Klisch
Keyword(s):  
Electron Microscopy ◽  
Stem Cells ◽  
Cell Types ◽  
Giant Cells ◽  
Morphological Characterization ◽  
Early Stages ◽  
Transmission Electron ◽  
Block Face ◽  
Trophoblast Giant Cells

Binucleate trophoblast giant cells (TGCs) are one characteristic feature of the ruminant placenta. In cows, the frequency of TGCs remains constant for most of the duration of pregnancy. As TGCs are depleted by their fusion with uterine epithelial cells, they need to be constantly formed. It is still unclear whether they develop from stem cells within the trophectoderm or whether they can arise from any uninucleate trophoblast cell (UTC). Within the latter, generally accepted theory, a basally located uninucleate cell (BUC) without contact to the feto-maternal interface would represent a transient cell between a UTC and a TGC. So far, no evidence for the existence of such transient cells or for the presence of stem cells has been shown. The aim of the present study is to morphologically characterize the early stages of TGC development. Placentomal tissue of 6 pregnant cows from different gestational stages (gestational days 51–214) was examined for BUCs, UTCs, and TGCs either in serial sections (light and transmission electron microscopy, TEM, n = 3), in single sections (TEM, n = 2), or by serial block face-scanning electron microscopy (n = 1). These investigations revealed the occurrence of BUCs, as well as young TGCs showing contact with the basement membrane (BM), but without apical contact to the feto-maternal interface. The study morphologically defines these 2 cell types as early stages of TGC development and shows that binucleation of TGCs can precede detachment from the BM.

71 WHAT IS THE UTERINE RESPONSE IN A CLONED BOVINE PREGNANCY?

2006 ◽  
Vol 18 (2) ◽  
pp. 144 ◽  
Author(s):  
T. C. Santos ◽  
F. T. V. Pereira ◽  
A. C. Assis Neto ◽  
C. E. Ambrósio ◽  
F. V. Meirelles ◽  
...  
Keyword(s):  
Cell Cycle ◽  
First Trimester ◽  
Giant Cells ◽  
Differential Analysis ◽  
Placental Development ◽  
Trophoblastic Cells ◽  
M Phase ◽  
Cell Cycle Phases ◽  
Cloned Bovine ◽  
Trophoblast Giant Cells

Bovine has a synepitheliochorial placenta and characteristically there is no invasion of the trophoblast, but there is migration of the binucleate trophoblast giant cells into the maternal endometrium. The feto-maternal interface occurs in placentome where a tridimensional organization permits interactions between maternal epithelium and trophoblast, and in the intercaruncular area it is possible to observe a few mini-placentomes and the uterine glands opening. The objective of the present investigation was to study the morphological aspects of the uterus in bovine that had a cloned cattle gestations to understand the differences with natural gestation. The uterus and fetal membranes from natural and cloned cattle gestations were collected, fixed in 10% formaldehyde, processed, and stained for light microscopy and immunohistochemistry. The morphological differences observed in the surrogate uterus were: extensive areas without placentome, hemorrhagic uterine areas, caruncular fusion giving a reduced number of caruncules, increase in size and weight (megacaruncules), and a significant number of mini-caruncules giving miniplacentomes (diameter < 1 cm). In particular the mini-placentome showed functional trophoblastic cells with PAS+ granules in the binucleate trophoblast giant cells and an intense subepithelial capillary organization in maternal and fetal sides. The normal and clone placentomal cell populations were analyzed throughout pregnancy. The population of tetraploid and diploid trophoblastic cells was stained; detached cell cycle and DNA content was measured in FL2 using a FACscalibur flow cytometric system. We determined the percentage of cells in apoptosis (sub-G1), quiescent cells (G0/G1), synthesis (S), and proliferative cells (G2/M) with the aid of ModFit software. In addition, a cell cycle differential analysis was performed, and the tetraploid population presented statistical differences in cell cycle phases and populations relative to the apoptosis rate for the first (7.5 � 3.1%), second (15.2 � 5.0%) and third (17.3 � 4.3%) trimesters. The number of apoptotic cells increased significantly during pregnancy stages. The results showed that first trimester presented the majority of its cells in the G0-G1 phase, starting the cell cycle. On the other hand, the second and third trimesters presented the majority of their cells in the G2-M phase, ending the cell cycle. The relationship between cell cycle phases/rate of apoptosis in mononucleate cells, days of normal and cloned pregnancy, the number of binucleate cells, and their metabolic activity as well as their developmental kinetics could be important data in several studies that involve placental development in natural pregnancy or that derived from laboratory-manipulated embryos. This work was supported by FAPESP and CNPq.

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 Placental Failure and Impaired Vasculogenesis Result in Embryonic Lethality for Neuropathy Target Esterase-Deficient Mice

2004 ◽  
Vol 24 (4) ◽  
pp. 1667-1679 ◽  
Author(s):  
Markus Moser ◽  
Yong Li ◽  
Kristina Vaupel ◽  
Doris Kretzschmar ◽  
Reinhart Kluge ◽  
...  
Keyword(s):  
Embryonic Stem ◽  
Cell Types ◽  
Giant Cells ◽  
Embryonic Lethality ◽  
Targeted Mutagenesis ◽  
Neuropathy Target Esterase ◽  
Placental Development ◽  
Complete Inactivation ◽  
Placental Failure ◽  
Vessel Development

ABSTRACT Age-dependent neurodegeneration resulting from widespread apoptosis of neurons and glia characterize the Drosophila Swiss Cheese (SWS) mutant. Neuropathy target esterase (NTE), the vertebrate homologue of SWS, reacts with organophosphates which initiate a syndrome of axonal degeneration. NTE is expressed in neurons and a variety of nonneuronal cell types in adults and fetal mice. To investigate the physiological functions of NTE, we inactivated its gene by targeted mutagenesis in embryonic stem cells. Heterozygous NTE+/− mice displayed a 50% reduction in NTE activity but underwent normal organ development. Complete inactivation of the NTE gene resulted in embryonic lethality, which became evident after gastrulation at embryonic day 9 postcoitum (E9). As early as E7.5, mutant embryos revealed growth retardation which did not reflect impaired cell proliferation but rather resulted from failed placental development; as a consequence, massive apoptosis within the developing embryo preceded its resorption. Histological analysis indicated that NTE is essential for the formation of the labyrinth layer and survival and differentiation of secondary giant cells. Additionally, impairment of vasculogenesis in the yolk sacs and embryos of null mutant conceptuses suggested that NTE is also required for normal blood vessel development.

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