Single cell RNA-seq of brain macrophages and microglia in mice lacking Notch3
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE192585 | GEO | 2022/03/31
REPOSITORIES: GEO
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Project description:In this single cell RNAseq analysis, we compared brain transcriptomes from Notch3 knock out and control.
2022-03-31 | GSE192510 | GEO
Project description:Single cell RNA-seq of brain macrophages and microglia in mice lacking Notch3
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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: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.
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Project description:Molecular mechanisms underlying the differentiation of brain mural cells from neural crest are poorly understood. We found that activation of Notch3 signaling in human pluripotent stem cell-derived neural crest (using lentiviral overexpression of the human Notch3 intracellular domain, N3ICD) was sufficient to direct the differentiation of mural cells. We used Notch3 ChIP-sequencing to identify cis-regulatory elements directly bound by the Notch3 transcriptional activation complex in this system.
2024-02-02 | GSE205212 | GEO
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.
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Project description:We aimed to identify novel therapeutic compounds (small molecules) to target microglia and macrophage NO production. We set up a screen using a library of 30.000 drug-like compounds in collaboration with the FEM. Using a microglia cell line and primary microglia and macrophages, we identified one compound that inhibits NO production after LPS stimulation. We have used this compound successfully in several in vitro and in vivo experiments, including in an animal model for stroke. The compound was tagged with a biotinylated linker in order to isolate the compound using strepdavidine beads after incubation with cells or with lysate to identify proteins that the compound was bound to.
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Project description:Mice deficient in NRROS exhibit neurological phenotype similar to ALS. Our previous work showed that in phagocytes, NRROS regulates the degradation of Nox2, the enzymatic component of the NADPH oxidase that generates reactive oxygen species. NRROS is expressed in phagocytes, including macrophages, neutrophils and microglia but not neurons. Previous results on RNA-sequencing from WT and NRRO KO CD11b+ population (NGS601) identified perivascular macrophage (pvm)-like expression profile in NRROS KO cells. FACS data revealed a loss of microglia and concomitant gain of pvm-like cells in the brains of NRROS KO mice.
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Project description:Single cell RNA-seq of brain cells in mice lacking Notch3
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