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The Wnt/ß-catenin axis modulates early BBB development by fine-tuning TGFß signalling through ADAMTSL2

ABSTRACT: The Wnt/ß-catenin pathway is orchestrating the development of the blood-brain barrier (BBB), but its downstream mediators have remained elusive. To identify potential effectors, we generated an endothelial cell specific Axin1 over-expressing mouse model, AOEiEC. We found that in AOEiE mice Wnt/ß-catenin signalling was down regulated leading to premature regression and remodelling without directly compromising BBB integrity. Interestingly, by comparing transcriptomes of endothelial cells from control and AOEiEC mice, we identified Adamtsl2 as a novel Wnt/ß-catenin-induced, secreted factor, important for stabilizing the cerebral vasculature during development. Importantly, loss-of-function and gain-of-function experiments revealed that Adamtsl2 alone was sufficient to rescue CNS vascular defects seen upon Wnt-signalling inhibition. Furthermore, using various cell and animal models we demonstrate that Adamtsl2 exerts its function by fine-tuning the TGFβ signalling pathway in CNS vessels. In conclusion, this study implicates Adamtsl2 as a mediator of Wnt/ß-catenin signalling during BBB development by linking it to TGFβ signalling.

ORGANISM(S): Mus musculus

PROVIDER: GSE77874 | GEO | 2019/01/31

REPOSITORIES: GEO

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ADAMTSL2, a missing link in Wnt/ß-catenin regulated CNS vascular development

Project description:Context dependent molecular cues shape the formation of the cerebral vascular network and the function of the blood-brain barrier (BBB). The Wnt/ß-catenin pathway is orchestrating CNS vascular development, but downstream mediators have not been characterized. Here we generated an endothelial cell-specific R26-Axin1 overexpression (AOE) mouse model to inhibit Wnt/ß-catenin signaling. In AOE mice we discovered that blockade of Wnt/ß-catenin pathway leads to premature regression and remodeling without compromising BBB integrity. Importantly, by comparing transcriptomes of endothelial cells from wildtype and AOE mice, we identified ADAMTSL2 as a novel Wnt/ß-catenin-induced, secreted factor, important for stabilizing the BBB during development. Zebrafish loss-of-function and gain-of-function models, further demonstrated that ADAMTSL2 is crucial for normal vascular development and could rescue vascular phenotypes in AOE zebrafish brains. In conclusion, the studies presented here reveal a hitherto unrecognized role of ADAMTSL2 as an endothelial cell-specific mediator of Wnt/ß-catenin signaling during CNS vascular development and BBB-formation.

2019-02-22 | GSE66848 | GEO

Mus musculus

Project description:The Wnt/ß-catenin axis modulates early BBB development by fine-tuning TGFß signalling through ADAMTSL2

| PRJNA311937 | ENA

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

Targeted deletion of astrocytic Nhe1 stimulates Wnt/β-catenin-mediated BBB repair and angiogenesis after ischemic stroke

Project description:Roles of reactive perivascular astrocytes in dysregulation of the blood-brain barrier (BBB) function and cerebral perfusion are not well defined. Here, we investigated transformation of reactive astrocyte function for vascular repair after ischemic stroke by targeted deletion of astrocytic Na+/H+ exchanger isoform 1 in Gfap-CreERT2+/-;Nhe1f/f (Nhe1 Astro-KO) mice. Control Gfap-CreERT2+/-;Nhe1f/f (wild-type) mice displayed BBB damage (elevated endothelial transcytosis and intracellular vesicles) and persistent cerebral hypoperfusion in an ischemic stroke model (transient middle cerebral artery occlusion). In contrast, Nhe1 Astro-KO mice exhibited significantly less endothelial transcytosis and vesicle formation, and increased angiogenesis and cerebral blood perfusion (CBF) post-stroke. Bulk RNA-sequencing transcriptome analysis of isolated GFAP+ reactive astrocytes from wild-type and Nhe1 Astro-KO ischemic brains revealed that ~177 genes were differentially upregulated, with the Wnt7a mRNA among the top upregulated genes, along with additional Wnt pathway genes (Wnt7b, Fzd9, Fzd10, and Ndp). Abundant Wnt7a/b and β-catenin protein expression was detected in cerebral vessels of Nhe1 Astro-KO ischemic brains but not in the wild-type brains. Selective activation of Wnt/β-catenin pathway in cerebral vessels of Nhe1 Astro-KO ischemic brains was further validated using the Wnt reporter line TCF/LEF::H2B-eGFP; Gfap-CreERT2+/-;Nhe1f/f mice. Lastly, the role of Wnt/β-catenin pathway in resistance of Nhe1 Astro-KO mice to stroke-mediated BBB damage was tested by administration of Wnt/β-catenin inhibitor XAV-939. Taken together, we report that transforming reactive astrocyte function by upregulating astrocytic Wnt/β-catenin signaling activity is a novel mechanism to reduce the BBB endothelial damage, stimulate vascular repair, and restore cerebral blood flow after ischemic stroke.

2020-12-08 | GSE145839 | GEO

Expression alterations induced by restoration of AXIN1 expression in SNU449 hepatocellular carcinoma cells

Project description:Aberrant activation of Wnt/β-catenin signaling is observed in numerous cancers. In hepatocellular carcinoma activating mutations in CTNNB1 (20-25%) or loss of function mutations in AXIN1 (10%), AXIN2 (2%) and APC (1-2%) are observed. All these mutations lead to aberrant stabilization of β-catenin, which constitutively activates downstream Wnt/β-catenin target genes and triggers a genetic program resulting in tumor formation. However, in relation to AXIN1 mutations some reports have challenged whether these indeed result in tumor growth by enhancing β-catenin signaling (e.g. PMID: 16964294, 29525529). Several alternative pathways have also been linked to AXIN1 (ENSG00000103126), such as TGFβ, SAPK/JNK, p53, YAP/TAZ and c-myc. To identify which one of these or other unknown signaling routes are linked to AXIN1, using CRISPR-Cas9 genome editing, we have successfully repaired the homozygous p.R712* AXIN1 mutation present in the SNU449 hepatocellular carcinoma cell line. Next, using RNA sequencing the RNA expression patterns of 3 independent repaired clones were compared with 3 clones retaining the AXIN1 mutation. Surprisingly, only 5 genes were significantly altered in the repaired clones, among which AXIN2, a well-established β-catenin target gene. Thus, this analysis leads to the surprising observation that a commonly observed mutation in a hepatocellular tumor suppressor gene, is associated with minimal alterations in gene expression, at least in the SNU449 cell line.

2019-01-01 | GSE119001 | 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

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

Brain endothelial GSDMD activation determines inflammatory BBB breakdown

Project description:The blood-brain barrier (BBB) protects the central nervous system (CNS) from external assaults by pathogenic or harmful substances. BBB impairment frequently occurs during infection, inflammatory, or other pathological conditions, which causes or exacerbates a wide range of CNS diseases. Using single cell transcriptomics, we show in this study that during systemic LPS challenges, brain endothelial cells undergo Gsdmd-mediated pyroptosis and impair the integrity of the BBB, leading to profound changes in the transcriptomic landscape of brain parenchymal populations. Analyses of the scRNA-seq dataset reveal that brain endothelial cells responded strongly to systemic LPS challenge. Further analyses of the transcriptional signatures revealed that the brain parenchymal populations displayed heterogeneous responses to BBB leakage accompanied by systemic inflammation.

2024-02-22 | GSE211099 | GEO

The kinase TNIK is an essential activator of Wnt target genes

Project description:Wnt signalling maintains the undifferentiated state of intestinal crypt/progenitor cells through the TCF4/ß-catenin activating transcriptional complex. In colorectal cancer, activating mutations in Wnt pathway components lead to inappropriate activation of the TCF4/ß-catenin transcriptional program and tumourigenesis in the gut epithelium. The mechanisms by which TCF4/ß-catenin activate key target genes are not well understood. Using a proteomics approach, we identified Tnik, a member of the Germinal centre kinase family, as a Tcf4 interactor in the proliferative crypts of mouse small intestine. Tnik is recruited to promoters of Wnt target genes in mouse crypts and in Ls174T colorectal cancer cells in a ß-catenin dependent manner. Depletion of TNIK and expression of TNIK kinase mutants abrogated TCF-LEF transcription, highlighting the essential role of the kinase activity in Wnt target gene activation. siRNA depletion of TNIK followed by expression array analysis demonstrated that TNIK is an essential and exclusive activator of Wnt induced transcriptional program. As an essential component in the TCF4/ß-catenin activator complex, the kinase TNIK may present an attractive candidate for drug targeting in colorectal cancer.

2009-08-13 | GSE17623 | GEO

Death Receptors DR6 and TROY Regulate Brain Vascular Development

Project description:Signaling events that regulate central nervous system (CNS) angiogenesis and blood-brain barrier (BBB) formation are only beginning to be elucidated. By evaluating the gene expression profile of mouse vasculature, we identified DR6/TNFRSF21 and TROY/TNFRSF19 as regulators of CNS-specific angiogenesis in both zebrafish and mice. Furthermore, these two death receptors interact both genetically and physically and are required for vascular endothelial growth factor (VEGF)-mediated JNK activation and subsequent human brain endothelial sprouting in vitro. Increasing beta-catenin levels in brain endothelium upregulate DR6 and TROY, indicating that these death receptors are downstream target genes of Wnt/beta-catenin signaling, which has been shown to be required for BBB development. These findings define a role for death receptors DR6 and TROY in CNS-specific vascular development. 5 replicates of 3 time points for either brain or liver/lung facs sorted vascaulture. One adult liver/lung replicate was not used as it failed QC

2012-02-15 | E-GEOD-35802 | biostudies-arrayexpress

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