Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Patterning and gastrulation defects caused by the tw18 lethal are due to loss of Ppp2r1a

ABSTRACT: The mouse t haplotype, a variant 20 cM genomic region on Chromosome 17, harbors sixteen embryonic control genes identified by recessive lethal mutations isolated from wild mouse populations. Due to technical constraints so far only one of these, the tw5 lethal has been cloned and molecularly characterized. Here we report the molecular isolation of the tw18 lethal. Embryos carrying the tw18 lethal die from major gastrulation defects commencing with primitive streak formation at E6.5. We have used transcriptome and marker gene analyses to describe the molecular etiology of the tw18 phenotype. We show that both WNT and Nodal signal transduction are impaired in the mutant epiblast causing embryonic patterning defects and failure of primitive streak and mesoderm formation. We have used a candidate gene approach, gene knockout by homologous recombination and genetic rescue to identify the gene causing the tw18 phenotype as Ppp2r1a, encoding the PP2A scaffolding subunit PR65. Our work highlights the importance of phosphatase 2A in embryonic patterning, primitive streak formation, gastrulation, and mesoderm formation downstream of WNT and Nodal signaling.

ORGANISM(S): Mus musculus

PROVIDER: GSE89734 | GEO | 2017/07/05

SECONDARY ACCESSION(S): PRJNA353031

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Mannose is crucial for mesoderm specification and symmetry breaking in gastruloids

Project description:Patterning and growth are fundamental features of embryonic development that must be tightly coordinated during morphogenesis. While metabolism is known to control cell growth, how it impacts patterning and links to morphogenesis is poorly understood. To understand how metabolism impacts early mesoderm specification during gastrulation, we used in vitro mouse embryonic stem (ES) cell-derived gastruloids, due to ease of metabolic manipulations and high-throughput nature. Gastruloids showed mosaic expression of glucose transporters co-expressing with the mesodermal marker T/Bra. To understand the significance of cellular glucose uptake in development, we used the glucose metabolism inhibitor 2-deoxy-D-glucose (2-DG). 2-DG blocked the expression of T/Bra and abolishes axial elongation in gastruloids. Surprisingly, removing glucose completely from the medium did not phenocopy 2-DG treatment despite a significant decline in glycolytic intermediates occurring under both conditions. As 2-DG can also act as a competitive inhibitor of mannose in protein glycosylation, we added mannose together with 2-DG and found that it could rescue the mesoderm specification. We corroborated these results in vivomouse embryos where supplementing mannose rescued the 2-DG mediated phenotype of mesoderm specification and proximo-distal elongation of the primitive streak. We further showed that blocking production and intracellular recycling of mannose abrogated mesoderm specification. At molecular level, proteomics analysis revealed that mannose reversed glycosylation of the Wnt pathway regulator, Secreted Frizzled Receptor, Frzb, expressed in the primitive streak of the mouse embryo. Our study showed how mannose linked metabolism to glycosylation of a developmental pathway component, crucial in patterning of mesoderm and morphogenesis of gastruloids.

2024-01-12 | MSV000093849 | MassIVE

PI3Kβ and β-Catenin mediate EZH2 removal from promoters controlling human ESC stemness and primitive streak gene expression

Project description:The mechanism governing the transition of human embryonic stem cells towards differentiated cells is only partially understood. To explore this transition, the activity and expression of the ubiquitous phosphoinositide-3-kinase (PI3K α and β) were modulated. This study reports a pathway that dismantles the repression imposed by the EZH2 polycomb repressor on an essential stemness gene, NODAL, and on transcription factors required at differentiation to trigger primitive streak formation. The primitive streak is the site where gastrulation begins to give rise to the three embryonic cell layers from which all human tissues derive. The pathway involves an essential PI3Kβ-non-catalytic action for control of active-RAC1 levels, c-Jun-Nterminal-kinase activation and nuclear β-CATENIN accumulation. β-CATENIN deposition at promoters triggers the release of EZH2 repressor permitting both stemness maintenance (through control of NODAL) and correct differentiation, by allowing primitive streak master genes expression. PI3Kβ -mediated epigenetic control of EZH2/β-CATENIN might be modulated to direct stem cell differentiation.

2022-07-27 | GSE202163 | GEO

Single Cell Expression Profiling Resolves the Transcriptional Programs of Early Mesoderm Diversification

Project description:We analyzed 1,205 cells from the epiblast and nascent mesoderm of gastrulating mouse embryos by single cell RNA-seq, representing the first transcriptome-wide in vivo view of mammalian gastrulation. Based on the distribution of key marker genes and their spatiotemporal expression patterns within the embryo, we identified 10 cell clusters corresponding to the epiblast and developing mesodermal populations. This enabled us to explore the global gene expression dynamics associated with the induction of Brachyury, anterior-posterior patterning of the primitive streak and the earliest stages of blood development. Examination of Gata1 binding in Runx1-ires-GFP+/Gata1-mCherry+ (primitive erythroid) cells derived from 5 days of differentiation of ESCs towards haematopoietic cells

2016-07-07 | E-GEOD-74994 | biostudies-arrayexpress

Dual gene activating and repressive functions of TET1 in germ layer lineage bifurcation distinguished by genomic context and dependence on 5-methylcytosine oxidation [10x scRNAseq]

Project description:Gastrulation initiates when the epiblast differentiates into either definitive ectoderm or primitive streak. During the lineage bifurcation, the DNA dioxygenase TET1 plays dual roles in both transcriptional activation and repression, but how it exerts this bipartite control via 5-methylcytosine (5mC) oxidation-dependent and independent activities remains unclear. Here, we perform a monolayer differentiation of mouse embryonic stem cells (ESCs) into neuronal precursors to define at single-cell resolution how Tet1-/- cells undergo a lineage switch to primitive streak and subsequently form mesoderm and endoderm. We identify the Wnt repressor Tcf7l1 as a direct target of TET1 that controls a signaling cascade of Wnt/β-catenin upstream of Nodal. Disrupting the endogenous catalytic site of Tet1 in ESCs contributes to activation of Nodal and subsequently Wnt/β-catenin signaling, promoting tri-lineage differentiation into ectoderm, mesoderm and endoderm. Catalytically dead TET1 is sufficient in sustaining open neuroectoderm enhancers, by which gene expression is uncoupled from enhancer DNA demethylation, and indirectly keeping primitive streak enhancers inaccessible to Wnt regulators and effectors. DNA hypermethylation caused by TET1 catalytic dysfunction instead promotes precocious primitive streak gene activation when associated with CpG islands overlapping bivalent gene promotors. Moreover, hypermethylated regions amplify in numbers in the absence of TET1 through differentiation to affect genes associated with neurological functions. Our results reveal two-way safeguarding activities of TET1 separable by genomic features, where at CpG-poor distal enhancers TET1 maintains accessible chromatin permissive for neural fate independently of 5mC oxidation; at CpG-rich bivalent promoters it prevents premature gene activation inducing alternative fates by harnessing 5mC oxidation in Polycomb gene repression.

2023-04-12 | GSE214844 | GEO

Dual gene activating and repressive functions of TET1 in germ layer lineage bifurcation distinguished by genomic context and dependence on 5-methylcytosine oxidation [RNAseq]

2023-04-12 | GSE214828 | GEO

Dual gene activating and repressive functions of TET1 in germ layer lineage bifurcation distinguished by genomic context and dependence on 5-methylcytosine oxidation [ATACseq 2]

2023-04-12 | GSE227231 | GEO

Dual gene activating and repressive functions of TET1 in germ layer lineage bifurcation distinguished by genomic context and dependence on 5-methylcytosine oxidation [RNAseq2]

2023-04-12 | GSE227236 | GEO

Dual gene activating and repressive functions of TET1 in germ layer lineage bifurcation distinguished by genomic context and dependence on 5-methylcytosine oxidation [CUT&RUN]

2023-04-12 | GSE227233 | GEO