E-GEOD-55203
Ontology highlight
ABSTRACT:
PROVIDER: E-GEOD-55203 | ExpressionAtlas | 2015-02-23
REPOSITORIES: ExpressionAtlas
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| E-GEOD-55203-analysis-methods.tsv | Tabular | |||
| E-GEOD-55203-atlasExperimentSummary.Rdata | Rdata | |||
| E-GEOD-55203-configuration.xml | Xml | |||
| E-GEOD-55203-percentile-ranks.tsv | Tabular | |||
| E-GEOD-55203.condensed-sdrf.tsv | Tabular |
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Project description:Vascular smooth muscle cells (VSMC) are important for contraction, blood flow distribution and regulation of blood vessel diameter, but to what extent they contribute to the integrity of blood vessels and blood-brain barrier function is less well understood. In this report, we explored the impact of the progressive loss of VSMC in the Notch3-/- mouse on blood vessel integrity in the central nervous system To explore the molecular consequences of the VSMC phenotype in Notch3-/- mice, we performed genome-wide transcriptional profiling of the brain vasculature in mutants and littermate controls using Affymetrix Mouse Genome 430 2.0 Array. Three Notch3 knockout and three littermate control mice at age of 2 months were used to profile the transcriptomes. Total RNA was extracted from cerebral and cerebellar microvascular fragments and hyrbridized separately on the Mouse Genome 430 2.0 Array according to standard procedures.
2015-02-18 | E-GEOD-55203 | biostudies-arrayexpress
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Project description:Notch3 is a transmembrane receptor which is critically important for the structure and myogenic response of distal arteries, particularly cerebral arteries. After activation of the receptor, the intracellular domain translocates in the nucleus to activate target genes transcription. In order to identify Notch3 target genes, we used microarrays to compare gene expression from caudal arteries (Notch3+/+ vs Notch3-/-) and selected down-regulated genes in Notch3-/- arteries.
2012-03-31 | GSE36437 | GEO
Project description:Notch3 is a transmembrane receptor which is critically important for the structure and myogenic response of distal arteries, particularly cerebral arteries. After activation of the receptor, the intracellular domain translocates in the nucleus to activate target genes transcription. In order to identify Notch3 target genes, we used microarrays to compare gene expression from caudal arteries (Notch3+/+ vs Notch3-/-) and selected down-regulated genes in Notch3-/- arteries. Caudal arteries were dissected from 1 month old Notch3+/+ and Notch3-/- mice. RNA was prepared with arteries pooled from three (AJ_N3WT_3, AJ_N3WT_4) or four (AJ_N3WT_1, AJ_N3KO_1, AJ_N3KO_2, AJ_N3KO_4) mice and hybridized on Mouse MOE430.2 Affymetrix chips. For each group (Notch3+/+ and Notch3-/-), three biological replicates were performed.
2012-03-30 | E-GEOD-36437 | biostudies-arrayexpress
Project description:Cerebral small vessel disease (SVD) is a prevalent disease of aging and a major contributor to stroke and dementia. The most commonly inherited SVD, CADASIL, is caused by dominantly acting cysteine-altering mutations in NOTCH3. These mutations change the number of cysteines from an even to an odd number, but the impact of these alterations on NOTCH3 protein structure remain unclear. Here, we prepared wildtype and four mutant recombinant NOTCH3 protein fragments to analyze the impact of CADASIL mutations on oligomerization, thiol status, and protein stability. Using gel electrophoresis, tandem MS/MS, and collision-induced unfolding, we find that NOTCH3 mutant proteins feature increased amounts of inappropriate disulfide bridges, reduced cysteines, and structural instability. Presence of a second protein factor, an N-terminal fragment of NOTCH3 (NTF), is capable of further altering disulfide statuses of both wildtype and mutant proteins, leading to increased numbers of reduced cysteines and further destabilization of NOTCH3 structure. In sum, these studies identify specific cysteine residues alterations and quaternary structure induced by CADASIL mutations in NOTCH3; further, we validate that reductive factors alter the structure and stability of this small vessel disease protein.
2022-05-20 | PXD031097 | Pride
Project description:While most cases of vascular dementia represent complex interactions between host genetics and environmental factors, mendelian forms of vascular dementia also exist. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a mendelian disease characterized by progressive vascular deterioration, cognitive deficits, and strokes. Mutations in the NOTCH3 receptor underlies the pathologies in CADASIL. NOTCH3 is primarily expressed in vascular smooth muscle cell (vSMC) and its’ expression is critical for differentiation and functional integrity of arterial vSMCs, albeit through unclear mechanism(s). To elucidate the contribution of NOTCH3 in the maintenance of cerebral vascular architecture and function, we performed micro-computed tomography (micro-CT) on the brains of aged Notch3-deficient animals. Micro-CT assessment of the cerebral vasculature architecture showed significant abnormalities including severe vessel dilation and tortuosity (dolicoectasia) of the middle cerebral artery and its branches in the Notch3-/- compared to aged-match controls. To identify the molecular pathway from NOTCH3 dysregulation to the observed cerebral vascular dysfunction, we performed single-cell RNASeq on cerebral arteries isolated from young (4w) and old (104w) Notch3-/- animals. Evaluation of the vSMC-specific transcriptomes indicated significant loss of proteins associated with muscle contraction and increased extracellular matrix production in animals that lack NOTCH3. Using a combination of immunofluorescence microscopy and in vitro functional assays, we confirmed that continued expression of Notch3 is a critical requirement for maintenance of vSMC contractile function. Impaired contractility also affected flow of cerebrospinal fluid in the parenchyma of Notch3-/- . MRI and behavioral assessments were performed in the Notch3-/- animals to elucidate the relationship between impaired vascular contractility to cognitive function. Taken together these findings link the molecular dysfunction of NOTCH3 through its regulation of vascular contractility and cerebral vessel architecture to altered neurological function and clarify the molecular pathways to cellular pathology of Notch3 driven dementias.
2024-01-17 | GSE204803 | GEO
Project description:Transcription profiling of mouse embryonic cells (E9.5) with homozygous knockout of Tbx1 compared to heterozygous Tbx1 knockout
2015-10-22 | E-MEXP-2096 | ExpressionAtlas
Project description:RNA-Seq analysis of E18.5 mouse Zfp800 knockout vs wild-type
2021-01-15 | E-MTAB-9538 | ExpressionAtlas
Project description:Transcription profiling of midbrain samples from Ezh2 knockout mouse embryos
2016-01-08 | E-GEOD-74538 | ExpressionAtlas
Project description:Loss of arterial smooth muscle cells (SMCs) and abnormal accumulation of the extracellular domain of the NOTCH3 (Notch3ECD) receptor are the two core features of CADASIL, the most common genetic cerebral small vessel disease. Although CADASIL is known to be caused by highly stereotyped dominant mutations in NOTCH3, the relationship between NOTCH3 receptor activity, Notch3ECD accumulation and arterial SMC loss has remained elusive, hampering the development of disease-modifying therapies. Using novel histopathological and multiscale imaging modalities, we quantified previously undetectable CADASIL-driven focal arterial SMC loss in the central nervous system of mice expressing the archetypal Arg169Cys CADASIL mutation. Notably, we found more severe arterial pathology and greater Notch3ECD accumulation in transgenic model mice overexpressing the mutation on a homozygous wild-type Notch3 background (TgNotch3R169C) than in knock-in model Notch3R170C/R170C mice expressing this mutation without a wild-type Notch3 copy. We further showed that wild-type Notch3ECD co-aggregated with mutant Notch3ECD and that elimination of one copy of wild-type Notch3 in TgNotch3R169C mice was sufficient to attenuate Notch3ECD accumulation and arterial pathology. Importantly, RNA sequencing revealed no substantial change in the expression of Notch3-regulated genes in TgNotch3R169C brain arteries. Collectively, our results provide compelling evidence that Notch3ECD accumulation, involving mutant and wild-type NOTCH3, and not aberrant NOTCH3 signaling, is the key driver of arterial SMC loss in CADASIL, thus identifying NOTCH3-lowering approaches as candidate therapeutic strategies.
2024-04-17 | GSE242794 | GEO