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Choroid plexus mast cells drive tumor-associated hydrocephalus

ABSTRACT: Tumor-associated hydrocephalus (TAH) is a common and lethal complication of brain metastases. Although other factors beyond mechanical obstructions have been suggested, the exact mechanisms are unknown. Using single-nucleus RNA-sequencing and spatial transcriptomics, we find that a distinct population of mast cells locate in the choroid plexus and dramatically increase during TAH. Genetic fate-tracing and intracranial mast cell-specific tryptase knockout showed that choroid plexus mast cells (CPMCs) disrupt cilia of choroid plexus epithelia via the tryptase-PAR2-FoxJ1 pathway and consequently increase cerebrospinal fluid production. Mast cells are also found in the human choroid plexus. Levels of tryptase in cerebrospinal fluid are closely associated with clinical severity of TAH. BMS-262084, an inhibitor of tryptase, can cross blood-brain-barrier, inhibits TAH in vivo and alleviates mast cell-induced damage of epithelial cilia in a human pluripotent stem cell-derived choroid plexus organoid model. Collectively, we uncover the function of CPMCs and provide an attractive therapy for TAH.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE207546 | GEO | 2023/11/22

REPOSITORIES: GEO

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OTX2 homeoprotein regulates adult choroid plexus activity

Project description:Choroid plexus secretes cerebrospinal fluid important for brain development and homeostasis. The OTX2 homeoprotein is critical for choroid plexus development and remains highly expressed in adult choroid plexus. Through RNA sequencing analyses of constitutive and conditional knockdown adult mouse models, we reveal putative roles for OTX2 in choroid plexus function, including cell signaling and adhesion, and show that it regulates the expression of factors secreted into cerebrospinal fluid, notably transthyretin. We also show that Otx2 expression impacts choroid plexus immune and stress responses, and also affects splicing which leads to changes in mRNA isoforms of proteins implicated in oxidative stress response and DNA repair. Through mass spectrometry analysis of OTX2 protein partners in the choroid plexus, and in known non-cell autonomous target regions such as visual cortex and subventricular zone, we identified putative targets involved in cell adhesion, chromatin structure and RNA processing. Thus, OTX2 retains important roles in choroid plexus function and brain homeostasis throughout life.

2021-08-31 | GSE157386 | GEO

Choroid Plexus Gene Expression in ApoE3 or ApoE4-Knockin Mouse Choroid Plexuses

Project description:Laser capture microdissected choroid plexuses were obtained and expression arrays were generated to investigate gene expression in ApoE-Knockin choroid plexuses; the choroid plexus forms the cerebrospinal fluid, the cerebrospinal fliod barrier, functions as the major gateway for blood-born leukocytes to enter the brain in degenerative and inflammatory brain diseases, and the principal neuroimmune interface in the brain. We found lipid deposits in the aged choroid plexus of hyperlipidemic ApoE4-Knockin mice but none in normolipidemic ApoE4-Knockin or normolipidemic or hyperlipidemic ApoE3-Knockin control choroid plexuses. Here, we studied the functional impact and gene epressions these choroid plexuses.

2018-11-20 | GSE85774 | GEO

Choroid Plexus Gene Expression in wild-type (wt) and ApoE-deficient Mouse Choroid Plexuses

Project description:Laser capture microdissected choroid plexuses were obtained and expression arrays were generated to investigate gene expression in wt and ApoE choroid plexuses; the choroid plexus forms the cerebrospinal fluid, the cerebrospinal fliod barrier, functions as the major gateway for blood-born leukocytes to enter the brain in degenerative and inflammatory brain diseases, and the principal neuroimmune interface in the brain. We found lipid deposits in the aged choroid plexus of hyperlipidemic mice but none in the wt control choroid plexuses. Here, we studied the functional impact and gene epressions in wt and ApoE-deficient choroid plexuses.

2018-11-20 | GSE85775 | GEO

Composition of the cerebrospinal fluid of normal and Mpdz-linked hydrocephalus-harboring mice

Project description:Though congenital hydrocephalus is heritable, it has been linked only to eight genes, one of which is MPDZ. Humans and mice that carry a truncated version of MPDZ incur severe hydrocephalus resulting in acute morbidity and lethality. We show by magnetic resonance imaging that contrast-medium penetrates into the brain ventricles of mice carrying a Mpdz loss-of-function mutation, whereas none is detected in the ventricles of normal mice, implying that the permeability of the choroid plexus epithelial cell monolayer is abnormally high. Comparative proteomic analysis of the cerebrospinal fluid of normal and hydrocephalic mice revealed up to a 53-fold increase in protein concentration, suggesting that transcytosis through the choroid plexus epithelial cells of Mpdz KO mice is substantially higher than in normal mice. These conclusions are supported by ultrastructural evidence, and by immunohistochemistry and cytology data. Our results provide a straightforward and concise explanation for the pathophysiology of Mpdz-linked hydrocephalus.

2018-11-23 | PXD011535 | Pride

Comparison of the Global Gene Expression of Choroid Plexus and Meninges and Associated Vasculature under Control Conditions and after Pronounced Hyperthermia or Amphetamine Toxicity

Project description:These tissue were harvested to complement and extend the studies that generated GSE23093. They served 3 purposes; 1) identify genes important to choroid plexus function and compare them with those important for meninges and associated vasculature (MAV) function, 2) determine genes in the choroid plexus and sensitivity hyperthermia and amphetamine toxicity, 3) identify the important gene expression changes related to the immune system in MAV, choroid plexus and trunk' blood Gene mRNA expression patterns in choroid plexus and trunk blood were determined under control conditions as well as after (3 hr and 1day) exposure to either environmentally-induced hyperthermia or neurotoxic doses of amphetamine. This data was analyzed and compared to data from meninges and associated vasculature previously deposited in GEO. The data gathered under control conditions was used to further understand how the choroid plexus and meninges and associated vasculature might function to generate and regulate the cerebrospinal fluid. The expression patterns in the choroid plexus after environmentally-induced hyperthermia or neurotoxic doses of amphetamine was determine its damage and protective responses. The expression patterns after environmentally-induced hyperthermia or neurotoxic doses of amphetamine were compared among choroid plexus, meninges and associated vasculature and blood were analyzed to determine immune system responses.

2012-08-01 | E-GEOD-29733 | biostudies-arrayexpress

Spatially heterogeneous choroid plexus transcriptomes encode positional identity and contribute to regional cerebrospinal fluid production

Project description:A sheet of choroid plexus epithelial cells extends into each cerebral ventricle and secretes signaling factors into the cerebrospinal fluid (CSF). To evaluate whether differences in the CSF proteome across ventricles arise, in part, from regional differences in choroid plexus gene expression, we defined the transcriptome of lateral ventricle (telencephalic) vs. fourth ventricle (hindbrain) choroid plexus. We find that positional identities of mouse, macaque, and human choroid plexi derive from gene expression domains that parallel their axial tissues of origin. We then show that molecular heterogeneity between telencephalic and hindbrain choroid plexi contributes to region-specific, age-dependent protein secretion in vitro. Transcriptome analysis of FACS-purified choroid plexus epithelial cells also predicts their cell type-specific secretome. Spatial domains with distinct protein expression profiles were observed within each choroid plexus. We propose that regional differences between choroid plexi contribute to dynamic signaling gradients across the mammalian cerebroventricular system.

2015-03-25 | GSE66312 | GEO

Effects of gut microbiota on gene expression in the choroid plexus

Project description:Accumulating evidence indicates that gut microbiota dysbiosis is associated with increased blood-brain barrier (BBB) permeability and contributes to Alzheimer’s disease (AD) pathogenesis. In contrast, the influence of gut microbiota on the blood-cerebrospinal fluid (CSF) barrier has not yet been studied. Here, RNA-seq analysis of choroid plexus tissues of normal colonized specific pathogen-free (SPF) versus decolonized antibiotics-treated mice revealed that the barrier function of choroid plexus is affected by the absence of gut microbiota in the AB mice.

2023-06-05 | GSE228655 | GEO

Brain heterotopia formation by ciliopathic breakdown of neuroepithelial and blood-cerebrospinal fluid barriers

Project description:In this study, we found that ablation of genes encoding ciliary transport proteins such as intraflagellar transport homolog 88 (Ift88) and kinesin family member 3a (Kif3a) in cortical radial progenitors led to periventricular heterotopia during late mouse embryogenesis. Conditional mutation of primary cilia unexpectedly caused breakdown of both the neuroepithelial lining and the blood-choroid plexus barrier. Choroidal leakage was partially caused by enlargement of the choroid plexus in the cilia mutants. We found that the choroid plexus expressed platelet-derived growth factor A (Pdgf-A) and that Pdgf-A expression was ectopically increased in cilia-mutant embryos. Cortices obtained from embryos in utero electroporated with Pdgfa mimicked periventricular heterotopic nodules of the cilia mutant.

2023-01-10 | PXD038557 | Pride

Gene expression study in choroid plexus

Project description:The choroid plexus (CP) constitutes one of the blood–brain barriers – the blood cerebrospinal fluid barrier. It is formed by a monolayer of epithelial cells located within the brain ventricles and in addition to be responsible for the formation of the cerebrospinal fluid (CSF) is ideally positioned to transmit signals into and out of the brain. Specifically, here, we evaluated the overall kinetic response of the mouse CP to peripheral administration of lipopolysaccharide (LPS) that is the Gram-negative bacteria cell wall. This study shows that as soon as 1h after the injection, the CP responds by altering the expression of several genes. This response reaches a maximum at 3h and returns to the basal profile for most of the transcripts at 72h. To do this analysis we compared the CP transcriptome of LPS injected animals with the CP transcriptome of saline injected animals and using this we also dissect the CP basal transcriptome. From this analysis we confirm that the genes most highly expressed were those implicated in energy metabolism (oxidative phosphorylation, glycolysis/gluconeogenesis) and in ribosomal function, which is in agreement with the secretory nature of the CP. Finally, we also describe genes not previously identified as being expressed in the basal CP. Gene expression study in choroid plexus. Time series after acute LPS treatment

2010-08-19 | E-GEOD-23714 | biostudies-arrayexpress

Choroid plexus defects in Down syndrome brain organoids enhance neurotropism of SARS-CoV-2

Project description:Why individuals with Down Syndrome (DS, trisomy 21) are particularly susceptible to SARS-CoV-2 induced disease remains largely unclear. The choroid plexus secrets the cerebrospinal fluid and strongly expresses the ACE2 receptor and the chromosome 21 encoded TMPRSS2 protease. To investigate the role of the choroid plexus in SARS-CoV-2 central nervous system infection in DS, we established a new type of brain organoid from DS and isogenic euploid control iPSC that consists of a core of appropriately patterned functional cortical neuronal cell types that is surrounded by a patent and functional choroid plexus (CPCOs). Remarkably, DS-CPCOs not only recapitulated abnormal features of DS cortical development but also revealed defects in ciliogenesis and epithelial cell polarity of the developing choroid plexus. We next demonstrate that the choroid plexus layer facilitates SARS-CoV-2 replication and infection of cortical neuronal cells, and that this is increased in DS-CPCOs. We further show that inhibition of TMPRSS2 activity in DS-CPCOs inhibits SARS-CoV-2 infectivity. We conclude that CPCOs are a useful model for dissecting the role of the choroid plexus in euploid and DS forebrain development and enables screening for therapeutics that can inhibit SARS-CoV-2 induced neuro-pathogenesis.

2023-10-16 | GSE208440 | GEO

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