Mosaic deletion of claudin-5 reveals rapid non-cell-autonomous consequences of blood-brain barrier leakage
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1053788 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27237267.fastq.gz | Fastqsanger.gz | |||
| SRR27237268.fastq.gz | Fastqsanger.gz | |||
| SRR27237269.fastq.gz | Fastqsanger.gz | |||
| SRR27237270.fastq.gz | Fastqsanger.gz | |||
| SRR27237271.fastq.gz | Fastqsanger.gz |
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Project description:Claudin-5 (CLDN5) is an endothelial tight junction protein essential for blood-brain barrier (BBB) formation. Abnormal CLDN5 expression is common in brain disease, and knockdown of Cldn5 at the BBB has been proposed to facilitate drug delivery to the brain. To study the consequences of CLDN5 loss in the mature brain, we induced mosaic endothelial-specific Cldn5 gene ablation in adult mice (Cldn5iECKO). These mice displayed increased BBB permeability to tracers up to 10 kDa in size from 7 days post induction (dpi) and ensuing lethality from 11 dpi. Single-cell RNA sequencing at 12 dpi revealed profound transcriptomic differences in brain endothelial cells regardless of their Cldn5 status in mosaic mice, suggesting major non-cell-autonomous responses. Reactive microglia and astrocytes suggested rapid cellular responses to BBB leakage. Our study demonstrates a critical role for CLDN5 in the adult BBB and provides molecular insight into the consequences and risks associated with CLDN5 inhibition.
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Project description:The tight junction (TJ) proteins claudin-2 and -10a form paracellular cation and anion channels, respectively, and have both been reported to be expressed in the proximal tubule (PT). However, the physiological role of claudin-10a in the kidney is yet obscure. Mice deficient in claudin-10a were generated and successful knockout was confirmed by Southern Blot, Western Blot and immunofluorescence staining. The functionality of isolated PTs was investigated electrophysiologically. Compensatory regulation was studied by pharmacological intervention, RNA-Seq analysis, Western Blot and immunofluorescence staining.
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Project description:To investigate the claudin-7 function in vivo, we generated a claudin-7 knockout mouse model by gene targeting through homologous recombination. In this study, we report that Cln7-/- pups show Na+, Cl-, and K+ wasting and chronic dehydration phenotypes. The dramatic increase of aldosterone synthase mRNA level suggests that these mice suffer from mishandling of NaCl and fluid in the distal nephrons. Deletion of claudin-7 invokes several compensatory changes, such as increased renin, serum-glucocorticoid-induced kinase 1 (SGK1), epithelial Na+ channel (ENaCα), Na+-Cl- cotransporter (NCC), as well as aquaporin (AQP) 2 mRNA levels, demonstrating the cross talks between paracellular and transcellular ion transport pathways.
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Project description:Mass spectrometry analysis confirmed the phosphorylation of human claudin-11 at tyrosine 191 and tyrosine 192
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Project description:Claudins are tight junction proteins that are involved in tight junction formation and function. Previous studies have shown that claudin-7 is frequently upregulated in epithelial ovarian cancer (EOC) along with claudin-3 and claudin-4. Here, we investigate in detail the expression patterns of claudin-7, as well as its possible functions in EOC. Initially a total of 95 ovarian tissue samples (7 normal ovarian tissues, 65 serous carcinomas, 11 clear cell carcinomas, 8 endometrioid carcinomas and 4 mucinous carcinomas) were studied for claudin-7 expression using RT-PCR analysis. The gene for claudin-7, CLDN7, was found to be significantly upregulated in all the tumor tissue samples studied. Similarly, immunohistochemical analysis and western blotting showed that claudin-7 protein was significantly overexpressed in the vast majority of EOCs. Two cell lines(OVCAR-2 and OVCA420) were chosen for microarray based gene expression analysis using small interfering RNA-mediated(SiRNA) knockdown of claudin-7. This treatment led to significant changes in gene expression that was validated by RT-PCR and immunoblotting.
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Project description:Healthy skin is a tapestry of wild-type and mutant clones. Although injury can cooperate with Ras mutations to promote tumorigenesis, the consequences in genetically mosaic skin are unknown. Here, we show that wild-type cells suppress oncogenic Ras-induced aberrant growth after injury. While HrasG12V/+ and KrasG12D/+ cells outcompete wild-type cells in uninjured, mosaic tissue, their expansion is prevented after injury due to an increase in the fraction of proliferating wild-type cells. Mechanistically, we show that, unlike HrasG12V/+ cells, wild-type cells respond to autocrine and paracrine secretion of EGFR ligands, and this differential activation of the EGFR pathway explains the competitive switch during injury-repair. Inhibition of EGFR by both drug and genetic approaches diminished the proportion of dividing wild-type cells after injury, leading to the expansion of HrasG12V/+ cells. Increased wild-type cell proliferation through a global loss of the cell cycle inhibitor p21 counteracted the expansion of HrasG12V/+ cells even without injury. Thus, injury plays an unanticipated role in switching the competitive balance between oncogenic and wild-type cells in genetically mosaic skin.
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Project description:Interactome study of the pan-claudin family by combining two complementary pull-down techniques followed by mass spectrometry to create an interaction landscape of the claudin family. Co-immunoprecipitation (CoIP) of recombinant claudins expressed in MDCK-C7 cells provided information about interactions beyond the already known TJ proteins. A protein interaction screen on a peptide matrix (PRISMA) allowed mapping interactions along the disordered cytosolic C-terminal region of claudins and studying the effect of post-translational modifications (PTMs) on these interactions. The new interaction partners of the C-terminus of several claudins were confirmed by proximity ligation assays (PLA) and revealed their possible implications in localized biological processes in epithelial cells. By combining these approaches, we created an extended interaction map of the claudin protein family, expanding the current knowledge in the field.
2023-10-24 | PXD031094 | Pride
Project description:Claudin proteins are major constituents of epithelial and endothelial tight junctions (TJ), where they serve as regulators of paracellular permeability to ions and solutes. Claudin-18, a member of the large claudin family, is highly expressed in lung epithelium. To elucidate the role of claudin-18 in alveolar epithelial barrier function and fluid homeostasis, we generated claudin-18 knockout (C18 KO) mice. Increased alveolar fluid clearance (AFC) observed in C18 KO mice may have accounted for absence of lung edema despite increased alveolar solute permeability compared to wild type (WT) controls. Higher AFC in C18 KO mice was associated with higher Na-K-ATPase activity and increased expression of the Na-K-ATPase β1 subunit compared to WT controls. Consistent with in vivo findings, alveolar epithelial cell (AEC) monolayers derived from C18 KO mice exhibited lower transepithelial electrical resistance (RT) accompanied by increased solute and ion permeability without changes in ion selectivity. Expression of claudin-3 and claudin-4 was markedly increased in whole lung and in freshly isolated AEC from C18 KO mice, while claudin-5 was unchanged. In contrast, occludin, another major component of the TJ complex, was significantly decreased in C18 KO lung. Further analysis revealed rearrangements in the F-actin cytoskeleton in C18 KO MAECM. These findings demonstrate a crucial non-redundant role for claudin-18 in regulation of alveolar epithelial tight junction composition and permeability to ions and solutes. Importantly, increased AFC in C18 KO mice identifies additional roles for claudin-18 in alveolar fluid homeostasis beyond its direct contributions to barrier properties of the alveolar epithelium.
2014-04-06 | GSE48443 | GEO
Project description:Claudin proteins are major constituents of epithelial and endothelial tight junctions (TJ), where they serve as regulators of paracellular permeability to ions and solutes. Claudin-18, a member of the large claudin family, is highly expressed in lung epithelium. To elucidate the role of claudin-18 in alveolar epithelial barrier function and fluid homeostasis, we generated claudin-18 knockout (C18 KO) mice. Increased alveolar fluid clearance (AFC) observed in C18 KO mice may have accounted for absence of lung edema despite increased alveolar solute permeability compared to wild type (WT) controls. Higher AFC in C18 KO mice was associated with higher Na-K-ATPase activity and increased expression of the Na-K-ATPase β1 subunit compared to WT controls. Consistent with in vivo findings, alveolar epithelial cell (AEC) monolayers derived from C18 KO mice exhibited lower transepithelial electrical resistance (RT) accompanied by increased solute and ion permeability without changes in ion selectivity. Expression of claudin-3 and claudin-4 was markedly increased in whole lung and in freshly isolated AEC from C18 KO mice, while claudin-5 was unchanged. In contrast, occludin, another major component of the TJ complex, was significantly decreased in C18 KO lung. Further analysis revealed rearrangements in the F-actin cytoskeleton in C18 KO MAECM. These findings demonstrate a crucial non-redundant role for claudin-18 in regulation of alveolar epithelial tight junction composition and permeability to ions and solutes. Importantly, increased AFC in C18 KO mice identifies additional roles for claudin-18 in alveolar fluid homeostasis beyond its direct contributions to barrier properties of the alveolar epithelium. Animals with a ubiquitous knockout (C18 KO) were obtained by crossing mice harboring a conditional (floxed) allele of claudin-18 (Cldn18F/F) with CMV-cre deleter mice to delete exons 2 and 3 by Cre/loxP recombination.
2014-04-06 | E-GEOD-48443 | biostudies-arrayexpress