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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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MRNA expression in HEK-293 /STF cells

ABSTRACT: Canonical Wnt signaling in endothelial cells (ECs) is required for vascularization of the central nervous system (CNS) and for formation and maintenance of barrier properties unique to CNS vasculature. Gpr124 is an orphan member of the adhesion G-protein-coupled receptor family that is expressed in ECs and is essential for CNS angiogenesis and barrier formation via an unknown mechanism. Using canonical Wnt signaling assays in cell culture and genetic loss- and gain-of-function experiments in mice, we show that Gpr124 functions as a co-activator of Wnt7a- and Wnt7b-stimulated canonical Wnt signaling via a Frizzled receptor and Lrp co-receptor, and that Gpr124-stimulated signaling functions in concert with Norrin/Frizzled4 signaling to control CNS vascular development. These experiments identify Gpr124 as a ligand-specific co-activator of canonical Wnt signaling. Total mRNA from HEK-293/STF cells was subjected to RNAseq

ORGANISM(S): Homo sapiens

SUBMITTER: Yulian Zhou

PROVIDER: E-GEOD-60529 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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mRNA expression in HEK-293 /STF cells

Project description:Canonical Wnt signaling in endothelial cells (ECs) is required for vascularization of the central nervous system (CNS) and for formation and maintenance of barrier properties unique to CNS vasculature. Gpr124 is an orphan member of the adhesion G-protein-coupled receptor family that is expressed in ECs and is essential for CNS angiogenesis and barrier formation via an unknown mechanism. Using canonical Wnt signaling assays in cell culture and genetic loss- and gain-of-function experiments in mice, we show that Gpr124 functions as a co-activator of Wnt7a- and Wnt7b-stimulated canonical Wnt signaling via a Frizzled receptor and Lrp co-receptor, and that Gpr124-stimulated signaling functions in concert with Norrin/Frizzled4 signaling to control CNS vascular development. These experiments identify Gpr124 as a ligand-specific co-activator of canonical Wnt signaling.

2014-08-20 | GSE60529 | GEO

RNA-sequencing of human pluripotent stem-cell derived endothelial cells under control and Wnt-activating conditions

Project description:Endothelial cells (ECs) in the central nervous system (CNS) acquire specialized barrier properties in response to extrinsic signals, with Wnt/β-catenin signaling coordinating multiple aspects of endothelial barrier function. We used human pluripotent stem cell (hPSC)-derived endothelial progenitor cells to profile the EC response to Wnt activation using multiple strategies, including the small molecule GSK-3 inhibitor CHIR 99021, and the CNS-derived ligands Wnt7a and Wnt7b.

2021-11-10 | GSE173206 | GEO

The transcriptional response to Norrin/Fz4 signaling

Project description:Using mice with targeted gene mutations, we identify (1) distinct roles for different canonical Wnt signaling components in central nervous system (CNS) vascular development and in the specification of the blood-brain and blood-retina barriers (BBB and BRB) and (2) differential sensitivities of the vasculature in various CNS regions to perturbations in canonical Wnt signaling components. We find nearly equivalent roles for Lrp5 and Lrp6 in brain vascular development and barrier maintenance but a dominant role for Lrp5 in the retinal vasculature, an especially high sensitivity of the BBB in the cerebellum and pons/interpeduncular nuclei to decrements in canonical Wnt signaling, and plasticity in the barrier properties of mature CNS vasculature. Brain and retinal vascular defects caused by loss of Norrin/Frizzled4 signaling can be fully rescued by stabilizing beta-catenin, and loss of beta-catenin’s transcriptional activation domain or expression of a dominant negative Tcf4 recapitulates the vascular development and barrier defects seen with loss of receptor, co-receptor, or ligand, indicating that Norrin/Frizzled4 signaling acts predominantly by beta-catenin-dependent transcriptional regulation. This work strongly supports a model in which identical or nearly identical canonical Wnt signaling mechanisms mediate neural tube and retinal vascularization and maintain the BBB and BRB. Total retina RNA from P10 WT, NdpKO, Ctnnb1flex3/+;Pdgfb-CreER, and NdpKO;Ctnnb1flex3/+;Pdgfb-CreER mice was subjected to RNAseq

2014-06-05 | E-GEOD-56461 | biostudies-arrayexpress

The transcriptional response to Norrin/Fz4 signaling

2014-06-05 | GSE56461 | GEO

Transcriptional and Epigenomic Landscapes of CNS and non-CNS Vascular Endothelial Cells

Project description:Vascular endothelial cell (EC) function depends on appropriate organ-specific molecular and cellular specializations. To explore genomic mechanisms that control this specialization, we have analyzed and compared the transcriptome, accessible chromatin, and DNA methylome landscapes from mouse brain, liver, lung, and kidney ECs. Analysis of transcription factor (TF) motifs at candidate cis-regulatory elements together with TF gene expression reveals both shared and organ-specific EC TFs. In the embryo, only those ECs that are adjacent to or within the developing CNS exhibit canonical Wnt signaling, which correlates precisely with blood-brain barrier (BBB) differentiation and Zic3 expression. In acutely cultured brain ECs, the rapid loss of BBB markers is closely correlated with down-regulation of canonical Wnt signaling. In the early postnatal brain, single cell RNA-seq of purified ECs reveals close relationships between veins and mitotic cells and between arteries and tip cells, and a division of capillary ECs into vein-like and artery-like classes.

2018-09-06 | GSE111839 | GEO

Epigenetic Mechanisms Regulating the Transcription of BBB Genes: Role of Wnt/β-catenin signaling

Project description:To identify in CNS endothelial cell (EC) the gene cohorts that participate in blood brain barrier (BBB) formation versus maintenance. We investigated mechanisms behind the reduced Wnt/β-catenin signaling observed in adult CNS ECs We also investigated whether the adult endothelial cells can re express the EC gene cohorts required for the BBB formation.

2022-11-03 | GSE214923 | GEO

Gpr124 is essential for blood-brain barrier integrity in central nervous system disease

Project description:Although blood-brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS) disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelial G protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adults is unknown. Here, conditional Gpr124 knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity but resulted in BBB disruption and microvascular hemorrhage in mouse models of ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt/beta-catenin signaling. Constitutive activation of Wnt/beta-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124 cko mice, with rescue of the endothelial tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption.

2017-03-06 | GSE74052 | GEO

Tetraspanin TSPAN12 regulates tumor growth and metastasis and inhibits b-catenin degedation

Project description:Ablation of tetraspanin protein TSPAN12 from human MDA-MB-231 cells resulted in a major decrease in primary tumor xenograft growth, accompanied by a significant increase in tumor apoptosis. Furthermore, TSPAN12 removal markedly increased metastasis to mouse lungs, due to enhanced tumor-endothelial interactions. Removal of TSPAN12 from human MDA-MB-231 cells also caused substantial proteosomal degradation of Î²-catenin, a key effecter of canonical Wnt signalling. This may be explained by TSPAN12 ablation leading to diminished association between FZD4 (a key receptor in the canonical Wnt pathway) and its co-receptor LRP5. Consistent with disruption of canonical Wnt signaling, TSPAN12 ablation altered the expression of LRP5, Naked 1 and 2, DVL2, DVL3, Axin 1 and GSKÎ²3 proteins, and also altered expression of several genes regulated by Î²-catenin. In conclusion, these results provide the first evidence for TSPAN12 playing a role in supporting primary tumor growth and suppressing metastasis. TSPAN12 appears to function by stabilizing FZD4-LRP5 association, in support of canonical Wnt-pathway signaling, leading to enhanced Î²-catenin expression and function. 4 samples = 2 Control + 2 TSPAN12KD

2012-10-29 | E-GEOD-41892 | biostudies-arrayexpress

A genome-wide view of the de-differentiation of central nervous system endothelial cells in culture

Project description:Vascular endothelial cells (ECs) derived from the central nervous system (CNS) variably lose their unique barrier properties during in vitro culture, hindering the development of robust assays for BBB function, including drug permeability and extrusion assays. In previous work (Sabbagh et al., 2018) we characterized transcriptional and accessible chromatin landscapes of acutely isolated CNS ECs. In this report, we compare transcriptional and accessible chromatin landscapes of acutely isolated CNS ECs versus CNS ECs in short-term in vitro culture. We observe that standard culture conditions are associated with a rapid and selective loss of BBB transcripts and chromatin features, as well as a greatly reduced level of beta-catenin signaling. Interestingly, forced expression of a stabilized derivative of beta-catenin, which in vivo leads to a partial conversion of non-BBB CNS ECs to a BBB-like state, has little or no effect on gene expression or chromatin accessibility in vitro.

2020-01-07 | GSE118731 | GEO

WNT7 Promotes Proliferation of Pancreatic Progenitor Cells Differentiated from Human Pluripotent Stem Cells through Non-Canonical Wnt Signaling Pathway

Project description:A small molecule, AT7867, promotes proliferation of human pluripotent stem cell-derived pancreatic progenitor cells (PPCs), yet detailed mechanisms of its proliferative effect were not fully understood. Here, we performed cell-based siRNA screening on a subset of genes to reveal that WNT7B is a growth factor of human PPCs as previously shown in mouse pancreas development. Although recombinant proteins had no in vitro activity, feeder cell lines stably expressing Wnt7a or Wnt7b enhanced PPC proliferation. Further analyses showed that canonical Wnt signaling pathway was not affected by AT7867 treatment as well as Wnt7a and Wnt7b. Knockdown of a non-canonical Wnt pathway component, PKCα, and its downstream substrate, MARCKS, blocked PPC proliferation suggesting a requirement of this pathway. Phosphoproteome analysis revealed that AT7867 inhibited Yin Yang 1 (YY1) phosphorylation at Ser118, which directly or indirectly regulated expression of WNT7B in PPCs. Taken together, non-canonical Wnt signaling mediated by WNT7B plays a critical role for the expansion of human PPC population that is a promising alternative cell source to generate β cells for the cure of diabetes.

2022-03-27 | PXD018222 | JPOST Repository

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