Wnt/β-catenin signaling controls development of the blood–brain barrier

The blood–brain barrier (BBB) is confined to the endothelium of brain capillaries and is indispensable for fluid homeostasis and neuronal function. In this study, we show that endothelial Wnt/β-catenin (β-cat) signaling regulates induction and maintenance of BBB characteristics during embryonic and postnatal development. Endothelial specific stabilization of β-cat in vivo enhances barrier maturation, whereas inactivation of β-cat causes significant down-regulation of claudin3 (Cldn3), up-regulation of plamalemma vesicle-associated protein, and BBB breakdown. Stabilization of β-cat in primary brain endothelial cells (ECs) in vitro by N-terminal truncation or Wnt3a treatment increases Cldn3 expression, BBB-type tight junction formation, and a BBB characteristic gene signature. Loss of β-cat or inhibition of its signaling abrogates this effect. Furthermore, stabilization of β-cat also increased Cldn3 and barrier properties in nonbrain-derived ECs. These findings may open new therapeutic avenues to modulate endothelial barrier function and to limit the devastating effects of BBB breakdown.

• Publication year

  2008

• Venue

  Journal of Cell Biology

• Publication date

  2008-11-03

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1083/jcb.200806024PMID 18955553PMCID 2575783
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5

  2008cited by this paper
• Efficient, inducible Cre‐recombinase activation in vascular endothelium

  2008influential reference
• Activation of β‐catenin signalling by GSK‐3 inhibition increases p‐glycoprotein expression in brain endothelial cells

  2008cited by this paper
• Puromycin‐purified rat brain microvascular endothelial cell cultures exhibit improved barrier properties in response to glucocorticoid induction

  2006cited by this paper
• Claudins in occluding junctions of humans and flies.

  2006cited by this paper
• Molecular mechanisms involved in T cell migration across the blood–brain barrier

  2006cited by this paper
• Regulation of Smooth Muscle Cell Proliferation by &bgr;-Catenin/T-Cell Factor Signaling Involves Modulation of Cyclin D1 and p21 Expression

  2006cited by this paper
• Plasmalemmal Vesicle Associated Protein-1 Is a Novel Marker Implicated in Brain Tumor Angiogenesis

  2005cited by this paper
• Wnt/beta-catenin pathway.

  2005cited by this paper
• -Catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse

  2004cited by this paper
• Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis

  2004influential reference
• Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice

  2004cited by this paper
• Mapping Wnt/β-catenin signaling during mouse development and in colorectal tumors

  2003cited by this paper
• Wnt proteins are lipid-modified and can act as stem cell growth factors

  2003cited by this paper
• Development of the blood-brain barrier

  2003cited by this paper
• The conditional inactivation of the β-catenin gene in endothelial cells causes a defective vascular pattern and increased vascular fragility

  2003cited by this paper
• Size-selective loosening of the blood-brain barrier in claudin-5–deficient mice

  2003cited by this paper
• Dishevelled 2 Recruits ß-Arrestin 2 to Mediate Wnt5A-Stimulated Endocytosis of Frizzled 4

  2003cited by this paper
• Localization of claudin-3 in tight junctions of the blood-brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme

  2003cited by this paper
• VE-cadherin regulates endothelial actin activating Rac and increasing membrane association of Tiam.

  2002cited by this paper
• Evans Blue Dye as an in vivo marker of myofibre damage: optimising parameters for detecting initial myofibre membrane permeability

  2002influential reference
• JCB Article

  2001influential reference
• Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus

  2001cited by this paper
• Inactivation of the beta-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development.

  2001influential reference
• Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme

  2000influential reference
• Correlation of tight junction morphology with the expression of tight junction proteins in blood-brain barrier endothelial cells.

  2000influential reference
• Alterations of Alzheimer's Disease in the Cholesterol‐fed Rabbit, Including Vascular Inflammation: Preliminary Observations

  2000cited by this paper
• The C-terminal transactivation domain of beta-catenin is necessary and sufficient for signaling by the LEF-1/beta-catenin complex in Xenopus laevis.

  1999cited by this paper
• Intestinal polyposis in mice with a dominant stable mutation of the β‐catenin gene

  1999cited by this paper
• The C-terminal transactivation domain of β-catenin is necessary and sufficient for signaling by the LEF-1/β-catenin complex in Xenopus laevis

  1999influential reference
• A Third-Generation Lentivirus Vector with a Conditional Packaging System

  1998cited by this paper
• Development of blood-brain barrier tight junctions in the rat cortex.

  1996cited by this paper
• Novel mouse endothelial cell surface marker is suppressed during differentiation of the blood brain barrier

  1995cited by this paper
• Monoclonal antibodies specific for endothelial cells of mouse blood vessels. Their application in the identification of adult and embryonic endothelium.

  1994cited by this paper

• Brain Pericytes and Wnt/β-Catenin Signaling Induce Functional Blood-Brain Barrier Phenotype in Human iPSC-Derived Model.

  2026cites this paper
• Pharmacological modulation of the blood-brain barrier: Mechanisms, therapeutic strategies, and emerging technologies.

  2026cites this paper
• Development of the blood–brain barrier

  2026cites this paper
• Scalable and multimodal brain angiogenesis and blood-brain barrier genetics by somatic mutagenesis.

  2026cites this paper
• ZIKV envelope protein is a strong blocker of early directional differentiation in the neural lineage.

  2026cites this paper
• Environmental enrichment and physical exercise prevent stress-induced social avoidance and blood-brain barrier alterations via Fgf2

  2026cites this paper
• Endothelial PROX1 induces blood-brain barrier disruption in the central nervous system

  2026cites this paper
• Cyflumetofen disrupts the blood-brain barrier and induces neurotoxicity in zebrafish larvae.

  2026cites this paper
• Strategies for blood-brain barrier rejuvenation and repair.

  2026cites this paper
• Canonical Wnt Signaling Suppresses Brain Endothelial Cell Transcytosis to Maintain Blood-Brain Barrier Integrity

  2025cites this paper
• The role of transcytosis in the blood-retina barrier: from pathophysiological functions to drug delivery

  2025cites this paper
• Associations of clinical indexes and prognosis with gut-vascular barrier damage in patients with intestinal obstruction

  2025cites this paper
• Generation of Advanced Blood–Brain Barrier Spheroids Using Human‐Induced Pluripotent Stem Cell‐Derived Brain Capillary Endothelial‐Like Cells

  2025cites this paper
• Decipher cell communication with attention: CLARA

  2025cites this paper
• Brain Endothelial Cells in Blood–Brain Barrier Regulation and Neurological Therapy

  2025influential citation
• A critical appraisal of drug transport across the blood-brain barrier: Evaluation using new-age microfluidic technique.

  2025cites this paper
• The Calcium Pump ATP2B1/PMCA1 Regulates CNS Vascular Development by Facilitating Norrin- and WNT7A/B-induced Frizzled4 signaling

  2025cites this paper
• Müller cell glutamine metabolism links photoreceptor and endothelial injury in diabetic retinopathy

  2025cites this paper
• Cellular Mechanisms Underlying Melanoma Brain Metastasis

  2025cites this paper
• WNT7A/B assemble a GPR124-RECK-LRP5/6 coreceptor complex to activate β-catenin signaling in brain endothelial cells

  2025cites this paper
• Across Barriers: Blood–Brain and Gut Barrier Signaling in Psychiatric Disorders

  2025influential citation
• The MDM2-p53 axis regulates norrin/frizzled4 signaling and blood-CNS barrier function.

  2025cites this paper
• Neuroinflammatory Loop in Schizophrenia, Is There a Relationship with Symptoms or Cognition Decline?

  2025cites this paper
• Development of perivascular astrocyte processes

  2025cites this paper
• Mechanisms of Astrocyte Action in the Blood Brain Barrier: From Structural Support to Dynamic Regulation.

  2025cites this paper
• Ref-1 redox activity modulates canonical Wnt signaling in endothelial cells

  2025cites this paper
• Blood-Brain Barrier: A Comprehensive Review of Its Structure, Function and Role in CNS Diseases

  2025cites this paper
• Deubiquitinase USP9X controls Wnt signaling for CNS vascular formation and barrier maintenance.

  2025cites this paper
• The Triad of Blood–Brain Barrier Integrity: Endothelial Cells, Astrocytes, and Pericytes in Perinatal Stroke Pathophysiology

  2025cites this paper
• IQGAP2 regulates blood-brain barrier immune dynamics

  2025cites this paper
• New genetic tools for central and peripheral vascular endothelia

  2025cites this paper
• Unravelling the Alzheimer's pathogenesis: Molecular and cellular pathways to neurodegeneration and therapeutic targets.

  2025cites this paper
• Phenotyping and genotyping FEVR: Molecular genetics, clinical and imaging features, and therapeutics.

  2025cites this paper
• Apelin as a CNS-specific pathway for fenestrated capillary formation in the choroid plexus

  2025cites this paper
• Mapping the transcriptional and epigenetic landscape of organotypic endothelial diversity in the developing and adult mouse

  2025cites this paper
• Keeping Wnt in check for efficient checkpoint blockade in glioblastoma

  2025cites this paper
• Breakdown of blood-brain barrier, astrocytic endfeet swelling, and abnormal behaviors by blockade of TROY signaling in TROY-Fc transgenic mice.

  2025cites this paper
• Mechanisms of parasite-mediated disruption of brain vessels.

  2025cites this paper
• [Effect of electroacupuncture on the permeability of blood-brain-barrier mediated by Wnt7a/β-catenin/GSK-3β pathway in mice with Parkinson's disease].

  2025cites this paper
• Endothelial Type I Interferon signaling modulates the vascular response to ischemic brain injury

  2025cites this paper
• Neurovascular dynamics in the spinal cord from development to pathophysiology.

  2025cites this paper
• Epigenetic Reactivation of CNS Endothelial Developmental Programs Triggers Adult Brain Angiogenesis, Promotes Post-Stroke Revascularization and Neuronal Regeneration

  2025cites this paper
• Cyclooxygenase-2 as a potential therapeutic target in the treatment of chemoresistant glioblastomas

  2025cites this paper
• Dynamic modulation of the blood–brain barrier in the healthy brain

  2025cites this paper
• Exercise training remodels inter-organ endocrine networks

  2025cites this paper
• Wnt signaling - using the bloodstream to send a message

  2025cites this paper
• IGF-1 Provides Protective Role in Arteriosclerotic Cerebral Small Vessel Disease

  2025cites this paper
• Targeting Alzheimer's pathophysiology with carbon dots: from mechanisms to therapy.

  2025cites this paper
• Disruption of small intestinal mucosal homeostasis in mice with amiodarone induced steatohepatitis

  2025cites this paper
• Circadian influences on central nervous system barriers and the glymphatic system

  2025cites this paper
• The Role of DKK-1 in HIV-Associated Neurocognitive Disorder: A Clinically Relevant Therapeutic Target

  2025cites this paper
• Inhibition of neutrophil extracellular traps alleviates blood–brain barrier disruption and cognitive dysfunction via Wnt3/β-catenin/TCF4 signaling in sepsis-associated encephalopathy

  2025cites this paper
• “PDGFRα is required for postnatal cerebral perivascular fibroblast development”

  2025cites this paper
• Exercise training remodels inter-organ endocrine networks

  2025cites this paper
• Keep your guard up: blood-brain barrier protection by empagliflozin after acute ischaemic stroke.

  2025cites this paper
• Plasma brain-related biomarkers and potential therapeutic targets in pediatric ECMO

  2025cites this paper
• Identification of Cell Fate Determining Transcription Factors for Generating Brain Endothelial Cells

  2025cites this paper
• Activation of Wnt/β-catenin in neural progenitor cells regulates blood–brain barrier development and promotes neuroinflammation

  2025cites this paper
• RECK as a Potential Crucial Molecule for the Targeted Treatment of Sepsis

  2025cites this paper
• Transcriptome and Functional Comparison of Primary and Immortalized Endothelial Cells of the Human Choroid Plexus at the Blood–Cerebrospinal Fluid Barrier

  2025cites this paper
• Endothelial PD‐1 Regulates Vascular Homeostasis and Oligodendrogenesis during Brain Development

  2025cites this paper
• Post-stroke depression: exploring gut microbiota-mediated barrier dysfunction through immune regulation

  2025cites this paper
• Predictive Value of circ_0020850 for Functional Outcomes After Acute Ischemic Stroke in Hospitalized Convalescent Patients.

  2025cites this paper
• Brain neurovascular unit in response to intra- and extra-central nervous system cancers: implications, mechanisms, and challenges

  2025cites this paper
• "PDGFRα is required for postnatal cerebral perivascular fibroblast development".

  2025cites this paper
• Wnt-Regulated Therapeutics for Blood-Brain Barrier Modulation and Cancer Therapy.

  2024cites this paper
• Key epigenetic and signaling factors in the formation and maintenance of the blood-brain barrier

  2024cites this paper
• Interplay between Netrin-1 and Norrin controls arteriovenous zonation of blood–retina barrier integrity

  2024cites this paper
• Pathogenesis of Germinal Matrix Hemorrhage: Insights from Single-Cell Transcriptomics.

  2024cites this paper
• ENDOTHELIAL PROX1 INDUCES BLOOD-BRAIN BARRIER DISRUPTION IN THE CENTRAL NERVOUS SYSTEM

  2024cites this paper
• Exploring complexities of Alzheimer's disease: New insights into molecular and cellular mechanisms of neurodegeneration and targeted therapeutic interventions.

  2024cites this paper
• The multifaceted therapeutical role of low‐density lipoprotein receptor family in high‐grade glioma

  2024cites this paper
• Compromised endothelial Wnt/β-catenin signaling mediates the blood-brain barrier disruption and leads to neuroinflammation in endotoxemia

  2024cites this paper
• Prenatal Exposure to Low Doses of Benzophenone-3 Elicits Disruption of Cortical Vasculature in Fetuses through Perturbations in Wnt/β-catenin Signaling Correlating with Depression-like Behavior in Offspring Mice.

  2024cites this paper
• Critical role of Slc22a8 in maintaining blood-brain barrier integrity after experimental cerebral ischemia-reperfusion

  2024cites this paper
• GPR126 is a specifier of blood-brain barrier formation in the mouse central nervous system

  2024cites this paper
• Dihydroartemisinin Modulates Enteric Glial Cell Heterogeneity to Alleviate Colitis

  2024cites this paper
• Single-cell atlas of the human brain vasculature across development, adulthood and disease

  2024cites this paper
• The Blood-Brain Barrier: Composition, Properties, and Roles in Brain Health.

  2024influential citation
• Pathophysiology in Brain Arteriovenous Malformations: Focus on Endothelial Dysfunctions and Endothelial-to-Mesenchymal Transition

  2024cites this paper
• Endothelial-to-Mesenchymal Transition in Cardiovascular Pathophysiology

  2024cites this paper
• Vascular development, remodeling and maturation.

  2024cites this paper
• Homeobox B4 optimizes the therapeutic effect of bone marrow mesenchymal stem cells on endotoxin-associated acute lung injury in rats.

  2024cites this paper
• An easy-to-perform method for microvessel isolation and primary brain endothelial cell culture to study Alzheimer's disease

  2024cites this paper
• Emerging Therapies for Glioblastoma

  2024cites this paper
• The Basic Requirement of Tight Junction Proteins in Blood-Brain Barrier Function and Their Role in Pathologies

  2024cites this paper
• Nanomodulators targeting endothelial WNT and pericytes to reversibly open the blood-tumor barrier for boosted brain tumor therapy.

  2024cites this paper
• Atorvastatin‐induced intracerebral hemorrhage is inhibited by berberine in zebrafish

  2024cites this paper
• Mechanical factors influence β-catenin localization and barrier properties.

  2024cites this paper
• Recombinant osteopontin stabilizes the blood brain barrier following subarachnoid hemorrhage in rats

  2024cites this paper
• Ginsenoside Rg1 protects the blood–brain barrier and myelin sheath to prevent postoperative cognitive dysfunction in aged mice

  2024cites this paper
• γ-Glutamylcysteine ameliorates blood-brain barrier permeability and neutrophil extracellular traps formation after ischemic stroke by modulating Wnt/β-catenin signalling in mice.

  2024cites this paper
• Suppressing Wnt signaling of the blood‒tumor barrier to intensify drug delivery and inhibit lipogenesis of brain metastases

  2024cites this paper
• Dahuang-Wumei decoction protects against hepatic encephalopathy in mice: Behavioural, biochemical, and molecular evidence.

  2024cites this paper
• IL-1β disrupts the initiation of blood-brain barrier development by inhibiting endothelial Wnt/β-catenin signaling

  2024cites this paper
• IQGAP2 regulates blood-brain barrier immune dynamics

  2024cites this paper
• Recapitulation of Structure–Function–Regulation of Blood–Brain Barrier under (Patho)Physiological Conditions

  2024cites this paper
• Modulation of miR-466d-3p on Wnt signaling pathway in response to DEPs-induced blood-brain barrier disruption.

  2024cites this paper
• Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets

  2024cites this paper
• Recent advances in tissue repair of the blood-brain barrier after stroke

  2024cites this paper