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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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE60529 | GEO | 2014/08/20

SECONDARY ACCESSION(S): PRJNA258471

REPOSITORIES: GEO

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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. Total mRNA from HEK-293/STF cells was subjected to RNAseq

2014-08-20 | E-GEOD-60529 | biostudies-arrayexpress

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.

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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

GPR124 regulates murine CNS angiogenesis and blood-brain barrier formation by an intracellular domain-independent mechanism

Project description:The GPR124/RECK/WNT7 pathway essentially regulates central nervous system angiogenesis and blood-brain barrier (BBB) function. GPR124, a brain endothelial adhesion 7-pass transmembrane protein, associates with membrane RECK, which binds and stabilizes newly synthesized WNT7 for subsequent transfer to Frizzled (FZD) and canonical b-catenin signaling. GPR124 function remains enigmatic; while its extracellular domain (ECD) is required, the poorly conserved intracellular domain (ICD) appears to be variably required in mammals versus zebrafish, potentially mediated by bridging of the GPR124 and FZD ICDs by intracellular adaptor proteins. GPR124 ICD deletion mutants impair zebrafish angiogenesis, but paradoxically still mediate WNT7 signaling upon mammalian cell transfection. We thus further investigated the GPR124 C-terminal ICD by deletion in mice (Gpr124ΔC). Notably, Gpr124ΔC/ΔC mice could be born and did not recapitulate Gpr124-/- embryonic lethal forebrain hemorrhage. GPR124ΔC protein was inefficiently expressed, resulting in mild, hypomorphic, non-hemorrhagic defects in CNS angiogenesis and BBB function, sparing the cortex and only confined to ganglionic eminences. Impaired surface expression of GPR124ΔC directly correlated with reduced endothelial WNT signaling, arguing against an intrinsic signaling deficiency. Further, GPR124ΔC and recombinant GPR124 ECD both rescued WNT7 signaling following brain endothelial Gpr124 knockdown. Thus, in mice, the GPR124 essential regulation of WNT7-dependent CNS forebrain angiogenesis and BBB function is exerted by ICD-independent functionality, extending the range of signaling mechanisms used by adhesion 7-pass transmembrane receptors.

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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

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.

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Project description:To address the role of endothelial Wnt/β-catenin signaling in CNS angiogenesis, we compared the bulk transcriptomes of WT and Wnt/β-catenin signaling-deficient PHBC endothelial cells, prior to CNS vascular invasion. To this end, we used three approaches to abrogate endothelial Wnt/β-catenin signaling: Morpholino-mediated knock-down of gpr124, reck or wnt7aa. We find that the expression of mmp25b is decreased in PHBC endothelial cells of all Wnt/β-catenin signaling deficient conditions as compared to the WT controls.

2024-02-07 | GSE233488 | 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.

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

Project description:To identify CNS endothelial cell (EC) the gene cohorts that participate in blood brain barrier (BBB) formation versus maintenance. We investigated mechanism 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.

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