MRNA expression changes in CCM3-deficient endothelial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE137425 | GEO | 2020/07/06
REPOSITORIES: GEO
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Project description:CCM3 regulates blood-brain-barrier integrity and vascular maturation in vivo. CCM3 loss-of-function variants predispose to cerebral cavernous malformations (CCM). Various signalling pathways are deregulated upon CCM3 depletion in endothelial cells (ECs). In this study, we established a crRNA:tracrRNA:Cas9 RNP approach to efficiently knockout CCM3 in human ECs and studied the molecular and functional effects of its long-term inactivation. Using small RNA sequencing, we show that CCM3 regulates the expression of aging‑associated miRNAs.
2019-01-18 | GSE114947 | GEO
Project description:Cerebral cavernous malformations (CCMs) are dilated capillaries causing epilepsy and stroke. Inheritance of a heterozygous mutation in CCM3/PDCD10 is responsible for the most aggressive familial form of the disease. Here we studied the differences and commonalities between the transcriptomes of microdissected lesional neurovascular units (NVUs) from acute and chronic in vivo Ccm3/Pdcd10ECKO mice, and cultured brain microvascular endothelial cells (BMECs) Ccm3/Pdcd10ECKO. We identified 2409 differentially expressed genes (DEGs) in acute and 2962 in chronic in vivo NVUs compared to microdissected brain capillaries, as well as 121 in in vitro BMECs with and without Ccm3/Pdcd10 loss (fold change ≥ |2.0|; p < 0.05, false discovery rate corrected). A functional clustered dendrogram generated using the Euclidean distance showed that the DEGs identified only in acute in vivo NVUs were clustered in cellular proliferation gene ontology functions. The DEGs only identified in chronic in vivo NVUs were clustered in inflammation and immune response, permeability, and adhesion functions. In addition, 1225 DEGs were only identified in the in vivo NVUs but not in vitro BMECs, and these clustered within neuronal and glial functions. One miRNA mmu-miR-3472a was differentially expressed (FC = -5.98; p = 0.07, FDR corrected) in the serum of Ccm3/Pdcd10+/- when compared to wild type mice, and this was functionally related as a putative target to Cand2 (cullin associated and neddylation dissociated 2), a DEG in acute and chronic lesional NVUs and in vitro BMECs. Our results suggest that the acute model is characterized by cell proliferation, while the chronic model showed inflammatory, adhesion and permeability processes. In addition, we highlight the importance of extra-endothelial structures in CCM disease, and potential role of circulating miRNAs as biomarkers of disease, interacting with DEGs. The extensive DEGs library of each model will serve as a validation tool for potential mechanistic, biomarker, and therapeutic targets.
2019-09-03 | GSE134006 | GEO
Project description:Cerebral cavernous malformations (CCMs) are dilated capillaries causing epilepsy and stroke. Inheritance of a heterozygous mutation in CCM3/PDCD10 is responsible for the most aggressive familial form of the disease. Here we studied the differences and commonalities between the transcriptomes of microdissected lesional neurovascular units (NVUs) from acute and chronic in vivo Ccm3/Pdcd10ECKO mice, and cultured brain microvascular endothelial cells (BMECs) Ccm3/Pdcd10ECKO. We identified 2409 differentially expressed genes (DEGs) in acute and 2962 in chronic in vivo NVUs compared to microdissected brain capillaries, as well as 121 in in vitro BMECs with and without Ccm3/Pdcd10 loss (fold change ≥ |2.0|; p < 0.05, false discovery rate corrected). A functional clustered dendrogram generated using the Euclidean distance showed that the DEGs identified only in acute in vivo NVUs were clustered in cellular proliferation gene ontology functions. The DEGs only identified in chronic in vivo NVUs were clustered in inflammation and immune response, permeability, and adhesion functions. In addition, 1225 DEGs were only identified in the in vivo NVUs but not in vitro BMECs, and these clustered within neuronal and glial functions. One miRNA mmu-miR-3472a was differentially expressed (FC = -5.98; p = 0.07, FDR corrected) in the serum of Ccm3/Pdcd10+/- when compared to wild type mice, and this was functionally related as a putative target to Cand2 (cullin associated and neddylation dissociated 2), a DEG in acute and chronic lesional NVUs and in vitro BMECs. Our results suggest that the acute model is characterized by cell proliferation, while the chronic model showed inflammatory, adhesion and permeability processes. In addition, we highlight the importance of extra-endothelial structures in CCM disease, and potential role of circulating miRNAs as biomarkers of disease, interacting with DEGs. The extensive DEGs library of each model will serve as a validation tool for potential mechanistic, biomarker, and therapeutic targets.
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Project description:Cerebral Cavernous Malformations (CCMs) are neurovascular lesions caused by loss-of-function mutations in one of three genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3). Following onset, disease severity ranges from minimal vascular defects to numerous vascular dilations (lesions) distributed throughout the brain. Although the precise pathogenic mechanisms resulting in such a broad range of disease severity are unknown, inter-cellular communication between heterogeneous brain cell types including microvascular endothelial cells, astrocytes, and neurons are likely important in disease progression. To further understand these cell type relationships in the context of CCM, Riboseq was performed in astroctytes and mRNA expression profiling was performed from whole brain extracts as well as isolated brain microvascular endothelial cells.
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Project description:Cerebral cavernous malformations are vascular anomalies that can cause hemorrhagic stroke. Mutations in genes encoding Krit 1 (CCM1), OSM (CCM2), and PDCD10 (CCM3) proteins cause CCM. A loss in teh expression of any of these CCM proteins disrupts normal cerebral vessel development by disrupting the cytoskeleton and thereby inhibits endothelial tube ofrmation. Examination of cellular changes based on the loss of CCM gene expression may lead to the methods for early detection and prevention of CCM associated hemorrhagic stroke.
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Project description:We report that loss of CCM3/PDCD10 in fibroblasts induces FAK/Src-paxillin signalling driving actomyosin-dependent mechanotransduction leading to YAP/TAZ signalling. In vivo, loss of CCM3 in fibroblasts drives excessive tissue remodelling leading to the dissemination of breast cancer cells to distant organs.
2021-05-06 | GSE155688 | GEO
Project description:Cerebral cavernous malformation (CCM) is caused by loss-of-function mutations in CCM1, CCM2, or CCM3 genes of endothelial cells. It is characterized by pericyte deficiency. However, the role of pericytes in CCMs remains poorly understood. Our study showed that pericytes in Cdh5CreERT2; Ccm1fl/fl (Ccm1ECKO) mice were high expression of PDGFRβ. The inhibition of pericyte function by CP-673451 aggravated the CCM lesion development. RNA-seq analysis revealed the molecular traits of pericytes, such as highly expressed ECM-related genes, especially Fn1. Furthermore, KLF4 coupled with phosphorylated SMAD3 promoted the transcription of fibronectin in pericytes of CCM lesions. RGDS peptide, an inhibitor of fibronectin, decreased the lesion area in the cerebella and retinas of Ccm1ECKO mice. Also, human CCM lesions had abundant fibronectin deposition, and pSMAD3- and KLF4-positive pericytes. The current data demonstrated that pericytes are essential for CCM lesion development, and fibronectin intervention may provide a novel target for therapeutic intervention in such patients.
2022-12-07 | GSE213244 | GEO
Project description:Primary cells deficient for PDCD10/CCM3 do not enter senescence as control cells. Microarray analysis was performed in cells transduced with non-targeting shRNA and CCM3 shRNA at passage 7 (early passage) and passage 11 (late passage), when control cells are already senescent. Primary endothelial cells were transduced either with non-target shRNA or with CCM3 shRNA. RNA was extracted at passage 7 and passage 11
2014-04-10 | E-GEOD-54095 | biostudies-arrayexpress
Project description:Using CRISPR/Cas9 genome editing and RNA sequencing, we demonstrate that fibronectin supplementation restores the impaired spheroid formation and attenuates actin stress fiber assembly in CCM3-/- endothelial cells independently of acute gene expression differences. In particular, there was no significant downregulation of well-known key players in CCM pathogenesis like KLF2 or KLF4.
2020-07-06 | GSE137426 | GEO
Project description:The GckIII pathway is a Hippo-like kinase module defined by sequential activation of Ste20 kinases Thousand and One (Tao) and Germinal Center Kinase III (GckIII), followed by nuclear dbf2-related (NDR) kinase Tricornered (Trc). We previously uncovered a role for the GckIII pathway in regulating tube morphology in the Drosophila melanogaster tracheal (respiratory) system. The trachea form a network of branched epithelial tubes essential for oxygen transport, and are structurally analogous to branched tubular organs in vertebrates, such as the vascular system. In the absence of GckIII pathway function, aberrant dilations form in tracheal tubes characterised by mislocalized junctional and apical proteins, suggesting that the GckIII pathway is important in maintaining tube integrity in development. Here, we observed a genetic interaction between trc and Cerebral cavernous malformations 3 (Ccm3), the Drosophila ortholog of a human vascular disease gene, supporting our hypothesis that the GckIII pathway functions downstream of Ccm3 in trachea, and potentially in the vertebrate cerebral vasculature. However, how GckIII pathway signalling is regulated and the mechanisms that underpin its function in tracheal development are unknown. We undertook biochemical and genetic approaches to identify proteins that interact with Trc, the most downstream GckIII pathway kinase. We found that known GckIII and NDR scaffold proteins are likely to control GckIII pathway signalling in tracheal development, consistent with their conserved roles in Hippo-like modules. Furthermore, we show genetic interactions between trc and multiple enzymes in glycolysis and oxidative phosphorylation, suggesting a potential function of the GckIII pathway in integrating cellular energy requirements with maintenance of tube integrity.
2023-03-13 | PXD038912 | Pride