RNA Microarray data from embryonic mouse brains wt vs foxf2 mutant
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Ali Nik
PROVIDER: E-GEOD-54531 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Brain of the foxf2 mutant mouse embryo shows microvascular aneurysm, underdeveloped blood brain barrier and also significant defects in the tissue integrity. Foxf2 expresses in the pericytes of the brain and seem to play an important role in proper development of the BBB.
2015-03-02 | GSE54531 | GEO
Project description:The blood-brain barrier (BBB) consists of specific physical barriers, enzymes and transporters, which together maintain the necessary extracellular environment of the central nervous system (CNS). The main physical barrier is found in the CNS endothelial cell, and depends on continuous complexes of tight junctions combined with reduced vesicular transport. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes, but the relative contribution of these different components to the BBB remains largely unknown. Here we demonstrate a direct role of pericytes at the BBB in vivo. Using a set of adult viable pericyte-deficient mouse mutants we show that pericyte deficiency increases the permeability of the BBB to water and a range of low-molecular-mass and high-molecular-mass tracers. The increased permeability occurs by endothelial transcytosis, a process that is rapidly arrested by the drug imatinib. Furthermore, we show that pericytes function at the BBB in at least two ways: by regulating BBB-specific gene expression patterns in endothelial cells, and by inducing polarization of astrocyte end-feet surrounding CNS blood vessels. Our results indicate a novel and critical role for pericytes in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the BBB. The brain microvascular fragments were isolated from mice with different genotypes, each represented by 3-4 biological replicates. Genotypes 1-2: Platelet derived growth factor-B (PDGF-B) retention-motif knockout (pdgfbret/ret) represent the pericyte-deficient situation, and the heterozygous mice (pdgfbret/+) are used as controls. Genotypes 3-4: Hypomorphic PDGF-B mutants that rescue pdgfb-/- null mice, in which a one copy of a conditionally silent human PDGF-B transgene targeted to the Rosa 26 locus (R26P) is turned on by endothelial-specific expression of Cre recombinase. In this data set these mice are named as Tie2Cre, R26P+/0, pdgfb-/- (representing the pericyte-deficient situation). Mice wt for pdgfb (pdgfb+/+) and carrying one silent copy of R26P (R26P+/0), are used as controls. Genotype 5: Adult Notch3+/+ wildtype (WT).
2010-10-21 | E-GEOD-15892 | biostudies-arrayexpress
Project description:PDGF-BB:PDGFRβ signalling in brain pericytes is critical to the development, maintenance and function of a healthy blood-brain barrier (BBB). Furthermore, BBB impairment and pericyte loss in Alzheimer’s disease (AD) is well documented. We used tissue microarrays from control and AD brains to determine if PDGF-BB:PDGFRβ signalling components were altered in AD, and found that there was a reduction in vascular expression of PDGFB. We hypothesised that reduced PDGF-BB:PDGFRβ signalling in pericytes may have an impact on functions related to the BBB. We therefore tested the effects of PDGF-BB on primary human brain pericytes in vitro to define important signalling pathways and outcomes related to BBB function. Pericytes demonstrate a biphasic response to PDGF-BB, predominantly dependent on Akt and ERK. We determined that the actions of PDGF-BB are on-target at PDGFRβ, leading to internalisation and degradation of PDGFRβ. Using pharmacological inhibitors, we dissected distinct aspects of the PDGF-BB response that are controlled by ERK and Akt pathways. PDGF-BB promotes the proliferation of pericytes and protection from toxic stimuli through ERK signalling. In contrast, PDGF-BB:PDGFRβ signalling through Akt and NF-κB augments pericyte-derived inflammatory secretions. It may therefore be possible to supplement PDGF-BB or small molecule agonists to stabilise the cerebrovasculature in AD.
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Project description:Reconstitution of a neurovascular unit model with blood-brain barrier (BBB) function is of great importance for drug development targeting cerebral diseases and study of brain disease mechanisms. In this study, we describe a human neurovascular unit chip designed by reconstituting necessary cellular and extracellular components in microfluidic devices. Dynamic three-dimensional co-culture of human cells (neural stem cells, brain microvascular endothelial cells, and brain vascular pericytes) in microfluidics with a stepwise unidirectional flow successfully established the chip with BBB-mimetic structural and functional features to be an effective barrier for drugs and cytokines. Furthermore, we showed the utility of the chip by modeling the neurotropic behaviors and BBB penetration process of a global fungal meningitis pathogen, Cryptococcus neoformans. This chip is the first in vitro experimental model for monitoring neurotropism of C. neoformans and would contribute to the investigation of various cerebral disorders, including microbial infectious diseases and their corresponding drug development.
2021-04-13 | GSE171937 | GEO
Project description:The blood-brain barrier (BBB) is a multicellular neurovascular unit (NVU) that allows the selective passage of necessary molecules into the central nervous system (CNS), while limiting the entry of neurotoxins and most drugs. A crosstalk with pericytes and neural cells mediates the acquisition of specialized properties, such as the formation of tight junctions (TJs), in brain microvascular endothelial cells (BMECs). TJs limit the paracellular passage of solutes, thereby regulating CNS homeostasis. However, the mechanisms by which NVU cells communicate to mediate TJ formation remains a mystery. Retinoic acid (RA), a key signaling molecule during vertebrate embryonic development, is commonly used to enhance functional barrier properties in in vitro BBB models. However, its physiological relevance and affected pathways are not fully understood.
2022-08-01 | GSE202485 | GEO
Project description:The aim of the present study was to analyze four different in vitro models of the murine BBB for expression and possible secretion of major basement membrane proteins from murine BCECs (mBCECs). The mBCECs and pericytes were isolated from brains of adult C57BL/6 mice, and glial cells (mainly astrocytes and microglia) were prepared from cerebral cortices of newborn C57BL/6 mice. The mBCECs were grown as mono-culture, in co-culture with pericytes or mixed glial cells, or as a triple-culture with both pericytes and mixed glial cells.
2016-08-03 | PXD003981 | Pride
Project description:Functional and structural dysfunction of the blood brain barrier (BBB) leads to severe alterations in brain physiology and is believed to trigger neurodegeneration. To investigate the molecular mechanisms driving the BBB dysfunction, very few human BBB cell culture models are available; of which, the human microvascular endothelial cell line (hCMEC/D3) is the most widely used. Thus far, array-based approaches or targeted seqeuncing based approaches have been employed to characterize the gene expression of the hCMEC/D3 model. However,The goal of this study is to perform deep transcriptomic sequencing of the BBB cell line and obtain features like gene expression, expressed single nucleotide variants, alternate splice forms, circular RNAs, long non-coding RNAs and micro RNAs. We have developed blood brain barriers transcriptomics landscape using RNA sequencing and micro RNA seqeuncing data obtained from replicates of hCMEC/D3 BBB cell line.
2016-03-17 | E-GEOD-76528 | biostudies-arrayexpress
Project description:Functional and structural dysfunction of the blood brain barrier (BBB) leads to severe alterations in brain physiology and is believed to trigger neurodegeneration. To investigate the molecular mechanisms driving the BBB dysfunction, very few human BBB cell culture models are available;of which, the human microvascular endothelial cell line (hCMEC/D3) is the most widely used. Thus far, array-based approaches or targeted seqeuncing based approaches have been employed to characterize the gene expression of the hCMEC/D3 model. However,The goal of this study is to perform deep transcriptomic sequencing of the BBB cell line and obtain features like gene expression, expressed single nucleotide variants, alternate splice forms, circular RNAs, long non-coding RNAs and micro RNAs. We have developed blood brain barriers transcriptomics landscape using RNA and micro RNA sequencing data obtained from replicates of hCMEC/D3 BBB cell line.
2016-03-17 | E-GEOD-76530 | biostudies-arrayexpress
Project description:The formation, maintenance, and repair of the blood-brain barrier (BBB) are critical for central nervous system homeostasis. The interaction of endothelial cells with brain pericytes is known to induce BBB characteristics in brain endothelial cells during embryogenesis and could be used to differentiate human endothelial cells from stem cell source in in vitro BBB models. However, the molecular events involved in BBB maturation are not fully understood. To this end, human endothelial cells derived from hematopoietic stem cells were cultivated with either primary bovine or cell line-derived human brain pericytes to induce BBB formation. Subsequently, the transcriptomic profiles of solocultured vs. cocultured endothelial cells were analyzed over time by the Massive Analysis of cDNA Ends (MACE) technology. This RNA sequencing method is a 3’-end targeted, tag-based, reduced representation transcriptome profiling technique that can reliably quantify all polyadenylated transcripts including those with low expression. By analyzing the generated transcriptomic profiles, we can explore the molecular processes responsible for the functional changes observed in endothelial cells in coculture with brain pericytes (e.g. barrier tightening, changes in the expression of transporters and receptors). Our results identified several up- and downregulated genes and signaling pathways that provide a valuable data source to further delineate complex molecular processes that are involved in BBB formation and BBB maintenance. In addition, this data provides a source to identify novel targets for central nervous system drug delivery strategies.
2020-08-05 | GSE144474 | GEO
Project description:Apolipoprotein E4 (APOE4), the main susceptibly gene for Alzheimer’s disease1–5, exerts cerebrovascular toxicity6 leading to blood-brain barrier (BBB) breakdown in humans7–9 and APOE4 transgenic mice10–13. Moreover, an early BBB dysfunction predicts cognitive decline in humans7. However, the comprehensive large-scale analysis of cell-specific mechanisms underlying APOE4 cerebrovascular disorder and how it relates to neuronal disorder is lacking. Using single-nucleus RNA-sequencing, phosphoproteome and proteome analysis14–17 here we show that APOE4 compared to APOE3 leads to early disruption of the BBB transcriptome in 2-3-month old APOE4 knock-in mice18 followed by dysregulation in protein signaling networks. This includes proteins regulating cell junctions, cytoskeleton, clathrin-mediated transport, and translation in brain endothelium, and transcription and RNA-splicing suggestive of DNA damage in pericytes. Changes in the BBB signaling mechanisms paralleled an early, progressive BBB breakdown and loss of pericytes starting at 2-3 months of age. The BBB breakdown preceded loss of neurites, post-synaptic interactome dysregulation, and behavioral deficits that developed 2-5 months later, and was associated with astrocyte and microglia response protecting BBB integrity. Thus, disruption of the BBB cell-specific signaling mechanisms could be an initial central contributor to APOE4-mediated neuronal disorder, and possibly a major target to correct APOE4-related cognitive deficits.
2022-08-23 | PXD029230 | Pride