Effects of gut microbiota on gene expression in the choroid plexus
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ABSTRACT: 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.
Project description:The choroid plexus produces cerebrospinal fluid (CSF) by transport of electrolytes and water from the vasculature to the brain ventricles. The choroid plexus plays additional roles in brain development and homeostasis by secreting neurotrophic molecules, and by serving as a CSF-blood barrier and immune interface. Prior studies have identified transporters on the epithelial cells that transport water and ions into the ventricles and tight junctions involved in the CSF-blood barrier. Yet, how the choroid plexus epithelial cells maintain the brain ventricle system and control brain physiology remain unresolved. To provide novel insights into the physiological roles of the choroid plexus, we use juvenile and adult zebrafish as model systems. Upon histological and transcriptomic analyses, we first identified that the zebrafish choroid plexus is highly conserved with the mammalian choroid plexus and that it expresses all transporters necessary for CSF secretion. Using novel genetic lines, we also identified that the choroid plexus secretes proteins into the CSF. Next, we generated a transgenic line allowing us to ablate specifically the epithelial cells in the choroid plexus. Using the ablation system, we identified a reduction of the ventricular sizes, but no alterations of the CSF-blood barrier. Altogether, our findings identified that the zebrafish choroid plexus is evolutionarily conserved and critical for maintaining the size and homeostasis of the brain ventricles.
Project description:Atoh1-Cre; Myc/Myc mice developed choroid plexus papilloma and Atoh1-Cre; Myc/Myc; p53fl/fl mice developed choroid plexus carcinoma. By studying the gene expression profiles of normal choroid plexus, choroid plexus papilloma and choroid plexus carcinoma in mice, we aim to gain a better understanding of the biology of choroid plexus tumors
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.
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.
Project description: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.
Project description:We report the transcription profiling of choroid plexus at 4 developmental stages, E12,5, P0, P14 and 6 month. We also compared wildtype and Foxj1-/- choroid plexus transcriptome at P0.
Project description:The human polyomavirus, JCPyV, establishes a lifelong persistent infection in the peripheral organs of a majority of the human population worldwide. Patients who are immunocompromised due to underlying infections, cancer, or to immunomodulatory treatments for autoimmune disease are at risk for developing progressive multifocal leukoencephalopathy (PML) when the virus invades the CNS and infects macroglial cells in the brain parenchyma. It is not yet known how the virus enters the CNS to cause disease. The blood-choroid plexus barrier is a potential site of virus invasion as the cells that make up this barrier are known to be infected with virus both in vivo and in vitro. To understand the effects of virus infection on these cells we challenged primary choroid plexus epithelial cells with JCPyV and profiled changes in host gene expression. We found that JC infection induced the expression of proinflammatory chemokines and downregulated junctional proteins essential for maintaining blood-CSF and blood-brain barrier function. These data contribute to our understanding of how virus infection of the choroid plexus can modulate the host cell response to neuroinvasive pathogens.
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
Project description:Gene expression profiles generated from human tumor cells laser-microdissected from surgical samples of seven choroid plexus papillomas (Grade I WHO) as eight samples of epithelial cells lasermicrodissected from normal choroid plexus obtained at autopsy. Choroid plexus tumors are rare pediatric brain tumors derrived from the choroid plexus epithelium. Gene expression profiles of lasermicrodissected tumor cells from 7 individual choroid plexus tumor samples obtained at surgery were compared to gene expression profiles from non-neoplastic choroid plexus epithelial cells lasermicrodissected from normal non-neoplastic choroid plexus obtained at autopsy (Am J Surg Pathol. 2006 Jan;30(1):66-74.) in order to identfy genes differentially expressed in choroid plexus tumor cells.