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Visceral endoderm expression of Yin-Yang1 (YY1) is required for VEGFA maintenance and yolk sac development.

ABSTRACT: Mouse embryos lacking the polycomb group gene member Yin-Yang1 (YY1) die during the peri-implantation stage. To assess the post-gastrulation role of YY1, a conditional knock-out (cKO) strategy was used to delete YY1 from the visceral endoderm of the yolk sac and the definitive endoderm of the embryo. cKO embryos display profound yolk sac defects at 9.5 days post coitum (dpc), including disrupted angiogenesis in mesoderm derivatives and altered epithelial characteristics in the visceral endoderm. Significant changes in both cell death and proliferation were confined to the YY1-expressing yolk sac mesoderm indicating that loss of YY1 in the visceral endoderm causes defects in the adjacent yolk sac mesoderm. Production of Vascular Endothelial Growth Factor A (VEGFA) by the visceral endoderm is essential for normal growth and development of the yolk sac vasculature. Reduced levels of VEGFA are observed in the cKO yolk sac, suggesting a cause for the angiogenesis defects. Ex vivo culture with exogenous VEGF not only rescued angiogenesis and apoptosis in the cKO yolk sac mesoderm, but also restored the epithelial defects observed in the cKO visceral endoderm. Intriguingly, blocking the activity of the mesoderm-localized VEGF receptor, FLK1, recapitulates both the mesoderm and visceral endoderm defects observed in the cKO yolk sac. Taken together, these results demonstrate that YY1 is responsible for maintaining VEGF in the developing visceral endoderm and that a VEGF-responsive paracrine signal, originating in the yolk sac mesoderm, is required to promote normal visceral endoderm development.

SUBMITTER: Rhee S

PROVIDER: S-EPMC3598950 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Loss of PiT-1 results in abnormal endocytosis in the yolk sac visceral endoderm.

Project description:PiT-1 protein is a transmembrane sodium-dependent phosphate (Pi) transporter. PiT-1 knock out (KO) embryos die from largely unknown causes by embryonic day (E) 12.5. We tested the hypothesis that PiT-1 is required for endocytosis in the embryonic yolk sac (YS) visceral endoderm (VE). Here we present data supporting that PiT-1 KO results in a YS remodeling defect and decreased endocytosis in the YS VE. The remodeling defect is not due to an upstream cardiomyocyte requirement for PiT-1, as SM22?Cre-specific KO of PiT-1 in the developing heart and the YS mesodermal layer (ME) does not recapitulate the PiT-1 global KO phenotype. Furthermore, we find that high levels of PiT-1 protein localize to the YS VE apical membrane. Together these data support that PiT-1 is likely required in YS VE. During normal development maternal immunoglobulin (IgG) is endocytosed into YS VE and accumulates in the apical side of the VE in a specialized lysosome termed the apical vacuole (AV). We have identified a reduction in PiT-1 KO VE cell height and a striking loss of IgG accumulation in the PiT-1 KO VE. The endocytosis genes Tfeb, Lamtor2 and Snx2 are increased at the RNA level. Lysotracker Red staining reveals a loss of distinct AVs, and yolk sacs incubated ex vivo with phRODO Green Dextran for Endocytosis demonstrate a functional loss of endocytosis. As yolk sac endocytosis is controlled in part by microautophagy, but expression of LC3 had not been examined, we investigated LC3 expression during yolk sac development and found stage-specific LC3 RNA expression that is predominantly from the YS VE layer at E9.5. Normalized LC3-II protein levels are decreased in the PiT-1 KO YS, supporting a requirement for PiT-1 in autophagy in the YS. Therefore, we propose the novel idea that PiT-1 is central to the regulation of endocytosis and autophagy in the YS VE.

| S-EPMC4207432 | biostudies-literature

Trinucleotide repeat containing 6a (Tnrc6a)-mediated microRNA function is required for development of yolk sac endoderm.

Project description:Tnrc6 family members (Tnrc6a/b/c) are key components of the RNA-induced silencing complex in microRNA (miRNA)-mediated gene suppression. Here, we show that Tnrc6a, also known as GW182, is selectively expressed in the yolk sac endoderm and that gene trap disruption of GW182 leads to growth arrest and apoptosis. We found that targets of miRNAs highly expressed in the yolk sac are significantly derepressed in GW182(gt/gt) mutant mice, although levels of miRNAs are not altered. Specifically, growth arrest and apoptosis phenotype are associated with significant derepression of Cdkn1a (p21), Cdkn1c (P27), Lats1, Lats2, Rb1, Rbl, Bim, and Pten, known targets of miRNAs from miR-17/20/93/106 clusters highly expressed in yolk sac endoderm. Together, these data strongly suggest that GW182 is an essential functional component in the RNA-induced silencing complex for miRNA-mediated gene silencing in vivo, and selectively regulation of miRNA activity plays an important role in the proper development of yolk sac.

| S-EPMC3285365 | biostudies-literature

Serum response factor is required for cell contact maintenance but dispensable for proliferation in visceral yolk sac endothelium.

Project description:BackgroundEndothelial-specific knockout of the transcription factor serum response factor (SRF) results in embryonic lethality by mid-gestation. The associated phenotype exhibits vascular failure in embryos as well as visceral yolk sac (VYS) tissues. Previous data suggest that this vascular failure is caused by alterations in cell-cell and cell-matrix contacts. In the current study, we sought to more carefully address the role of SRF in endothelial function and cell contact interactions in VYS tissues.ResultsTie2-Cre recombinase-mediated knockout of SRF expression resulted in loss of detectable SRF from VYS mesoderm by E12.5. This loss was accompanied by decreased expression of smooth muscle alpha-actin as well as vascular endothelial cadherin and claudin 5, endothelial-specific components of adherens and tight junctions, respectively. Focal adhesion (FA) integrins alpha5 and beta1 were largely unchanged in contrast to loss of the FA-associated molecule vinculin. The integrin binding partner fibronectin-1 was also profoundly decreased in the extracellular matrix, indicating another aspect of impaired adhesive function and integrin signaling. Additionally, cells in SRF-null VYS mesoderm failed to reduce proliferation, suggesting not only that integrin-mediated contact inhibition is impaired but also that SRF protein is not required for proliferation in these cells.ConclusionsOur data support a model in which SRF is critical in maintaining functional cell-cell and cell-matrix adhesion in endothelial cells. Furthermore, we provide evidence that supports a model in which loss of SRF protein results in a sustained proliferation defect due in part to failed integrin signaling.

| S-EPMC3065428 | biostudies-literature

Autotaxin/lysophospholipase D-mediated lysophosphatidic acid signaling is required to form distinctive large lysosomes in the visceral endoderm cells of the mouse yolk sac.

Project description:Autotaxin, a lysophospholipase D encoded by the Enpp2 gene, is an exoenzyme that produces lysophosphatidic acid in the extracellular space. Lysophosphatidic acid acts on specific G protein-coupled receptors, thereby regulating cell growth, migration, and survival. Previous studies have revealed that Enpp2(-/-) mouse embryos die at about embryonic day (E) 9.5 because of angiogenic defects in the yolk sac. However, what cellular defects occur in Enpp2(-/-) embryos and what intracellular signaling pathways are involved in the phenotype manifestation remain unknown. Here, we show that Enpp2 is required to form distinctive large lysosomes in the yolk sac visceral endoderm cells. From E7.5 to E9.5, Enpp2 mRNA is abundantly expressed in the visceral endoderm cells. In Enpp2(-/-) mouse embryos, lysosomes in the visceral endoderm cells are fragmented. By using a whole embryo culture system combined with specific pharmacological inhibitors for intracellular signaling molecules, we show that lysophosphatidic acid receptors and the Rho-Rho-associated coiled-coil containing protein kinase (ROCK)-LIM kinase pathway are required to form large lysosomes. In addition, electroporation of dominant negative forms of Rho, ROCK, or LIM kinase also leads to the size reduction of lysosomes in wild-type visceral endoderm cells. In Enpp2(-/-) visceral endoderm cells, the steady-state levels of cofilin phosphorylation and actin polymerization are reduced. In addition, perturbations of actin turnover dynamics by actin inhibitors cytochalasin B and jasplakinolide result in the defect in lysosome formation. These results suggest that constitutive activation of the Rho-ROCK-LIM kinase pathway by extracellular production of lysophosphatidic acid by the action of autotaxin is required to maintain the large size of lysosomes in visceral endoderm cells.

| S-EPMC2785199 | biostudies-literature

Imprinted expression is different in visceral yolk sac and cystic embryoid body endoderm

Project description:Genomic imprinting is an epigenetic phenomenon resulting in parent-of-origin mono-allelic expression of a small subset of mammalian genes. Imprinted genes have been categorized into two groups: multi lineage (ML) imprinted genes that can show imprinted expression in both embryonic and extra-embryonic lineages, and genes that show extra-embryonic lineage (EXEL) specific imprinted expression restricted to tissues like the placenta and visceral yolk sac (VYS) endoderm. Many genes showing EXEL imprinted expression are silenced by lncRNAs that act over long distances. Thus the analysis of this form of gene silencing is likely to be pivotal for understanding new mechanisms of long range gene silencing by lncRNAs. It has been reported that ES cells differentiated into cystic embryoid bodies (cystic EBs) contain VYS endoderm and here we investigate if cystic EBs could serve as an in vitro model for the analysis of EXEL imprinted expression. Unexpectedly we found that cystic EBs lack EXEL imprinted expression, while retaining normal imprinted expression of ML genes. This shows that cystic EBs do not model VYS imprinted expression and also argues against previous claims that cystic EBs contain VYS endoderm. We further characterized cystic EBs by performing RNA-seq and whole genome bisulphite sequencing. By comparison to various embryonic tissues we found that cystic EBs more resemble embryonic liver, which contains definitive endoderm, than the extra-embryonic endoderm of the VYS. Examination of gene and retrotranssposone expression and DNA methylation in extraembryonic, embryonic tissues and ES cell diferentiated as cystic EBs

2015-07-22 | E-GEOD-56276 | biostudies-arrayexpress

Imprinted expression is different in visceral yolk sac and cystic embryoid body endoderm

2015-07-22 | GSE56276 | GEO

Vacuolar-type proton ATPase is required for maintenance of apicobasal polarity of embryonic visceral endoderm.

Project description:The endocytic compartments keep their interior acidic through the inward flow of protons and anions from the cytosol. Acidification is mediated by a proton pump known as vacuolar-type ATPase (V-ATPase) and transporters conferring anion conductance to the organellar membrane. In this study, we analysed the phenotype of mouse embryos lacking the V-ATPase c-subunit. The mutant embryos differentiated embryonic epithelial tissues, primitive endoderm, epiblast, and extraembryonic ectoderm; however, the organisation of these epithelia was severely affected. The apical-basal polarity in the visceral endoderm layer was not properly established in the mutant embryos, resulting in abnormal epithelial morphology. Thus, the function of V-ATPase is imperative for the establishment and/or maintenance of epithelial cell polarity, which is required for early embryogenesis.

| S-EPMC8481250 | biostudies-literature

Integrins are required for the differentiation of visceral endoderm.

Project description:Integrins of the beta1 subfamily are highly expressed in the early mouse embryo and are essential for the formation of primitive germ layers from the inner cell mass (ICM). We investigated the mechanisms by which alphabeta1 integrins regulate ICM morphogenesis by using the embryonic-stem-cell-derived embryoid body (EB), a model for peri-implantation development. Ablation of integrin beta1 in EBs resulted in endoderm detachment and in maturation defects, which were manifested by the mislocalization of GATA4 in the cytoplasm and the markedly reduced synthesis of basement membrane (BM) components and the lineage marker disabled homolog 2. The mutant endoderm cells failed to spread on BM substrates, but could spread on vitronectin, which induced upregulation of alphavbeta3 integrin and integrin-dependent GATA4 nuclear translocation. Forced expression of integrin beta3 in the mutant EBs completely rescued endoderm morphogenesis, suggesting that integrin beta3 can substitute for integrin beta1 in the endoderm. Furthermore, the mitogen-activated protein kinases (MAPKs) ERK1 and ERK2 (ERK1/2) and p38 were activated in endoderm in an integrin-dependent fashion. Pharmacological inhibition of ERK1/2 or p38 MAPK blocked vitronectin-induced GATA4 nuclear translocation and endoderm maturation, whereas expression of a constitutively active ERK kinase (MEK1) or p38 MAPK in the mutant cells rescued endoderm maturation in integrin-beta1-null endoderm cells. Collectively, these results suggest that integrins are required for both the stable adhesion and maturation of visceral endoderm, the latter being mediated through the activation of ERK1/2 and p38 MAPK.

| S-EPMC2714419 | biostudies-literature

Aberrant lipid accumulation in the mouse visceral yolk sac resulting from maternal diabetes and obesity.

Project description:Maternal diabetes and obesity in pregnancy are well-known risk factors for structural birth defects, including neural tube defects and congenital heart defects. Progeny from affected pregnancies are also predisposed to developing cardiometabolic disease in later life. Based upon in vitro embryo cultures of rat embryos, it was postulated that nutrient uptake by the yolk sac is deficient in diabetic pregnancies. In contrast, using two independent mouse models of maternal diabetes, and a high-fat diet-feeding model of maternal obesity, we observed excessive lipid accumulation at 8.5 days in the yolk sac. The numbers as well as sizes of intracellular lipid droplets were increased in yolk sacs of embryos from diabetic and obese pregnancies. Maternal metabolic disease did not affect expression of lipid transporter proteins, including ApoA1, ApoB and SR-B1, consistent with our earlier report that expression of glucose and fatty acid transporter genes was also unchanged in diabetic pregnancy-derived yolk sacs. Colocalization of lipid droplets with lysosomes was significantly reduced in the yolk sacs from diabetic and obese pregnancies compared to yolk sacs from normal pregnancies. We therefore conclude that processing of lipids is defective in pregnancies affected by maternal metabolic disease, which may lead to reduced availability of lipids to the developing embryo. The possible implications of insufficient supply of lipids -and potentially of other nutrients-to the embryos experiencing adverse pregnancy conditions are discussed.

| S-EPMC10014468 | biostudies-literature

Modelling post-implantation human development to yolk sac blood emergence.

Project description:Implantation of the human embryo begins a critical developmental stage that comprises profound events including axis formation, gastrulation and the emergence of haematopoietic system1,2. Our mechanistic knowledge of this window of human life remains limited due to restricted access to in vivo samples for both technical and ethical reasons3-5. Stem cell models of human embryo have emerged to help unlock the mysteries of this stage6-16. Here we present a genetically inducible stem cell-derived embryoid model of early post-implantation human embryogenesis that captures the reciprocal codevelopment of embryonic tissue and the extra-embryonic endoderm and mesoderm niche with early haematopoiesis. This model is produced from induced pluripotent stem cells and shows unanticipated self-organizing cellular programmes similar to those that occur in embryogenesis, including the formation of amniotic cavity and bilaminar disc morphologies as well as the generation of an anterior hypoblast pole and posterior domain. The extra-embryonic layer in these embryoids lacks trophoblast and shows advanced multilineage yolk sac tissue-like morphogenesis that harbours a process similar to distinct waves of haematopoiesis, including the emergence of erythroid-, megakaryocyte-, myeloid- and lymphoid-like cells. This model presents an easy-to-use, high-throughput, reproducible and scalable platform to probe multifaceted aspects of human development and blood formation at the early post-implantation stage. It will provide a tractable human-based model for drug testing and disease modelling.

| S-EPMC10849971 | biostudies-literature

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