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: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:Aggresome is a para nuclear inclusion body that functions as a storage compartment for misfolded proteins. Our previous work revealed the presence of aggresomes in pediatric choroid plexus tumors (CPT). CPTs are rare neoplasms comprised of three pathological subgroups; choroid plexus carcinoma (CPC), a grade III tumor, atypical choroid plexus papilloma (ACPP), a grade II tumor, and choroid plexus papilloma (CPP), a grade I tumor. In the current study, we aimed to investigate the prognostic value of aggresomes-positivity and its correlation to the pathological and molecular subtypes. The proteomics profiling of 21 CPT pediatric samples was investigated using ABSciex Triple TOF 5600+ mass spectrometer.
Project description:Aggresome is a para nuclear inclusion body that functions as a storage compartment for misfolded proteins. Our previous work revealed the presence of aggresomes in pediatric choroid plexus tumors (CPT). CPTs are rare neoplasms comprised of three pathological subgroups; choroid plexus carcinoma (CPC), a grade III tumor, atypical choroid plexus papilloma (ACPP), a grade II tumor, and choroid plexus papilloma (CPP), a grade I tumor. In the current study, we aimed to investigate the prognostic value of aggresomes-positivity and its correlation to the pathological and molecular subtypes. The genome-wide methylation profile of 42 CPT pediatric samples was investigated using Illumina Infinium Methylation EPIC BeadChip array.
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.
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.
Project description:The choroid plexus is an important source of trophic factors for the developing and mature brain. Recently we described the expression and production of mature insulin in epithelial cells of the choroid plexus, and how its secretion can be modulated by serotonin through Htr2c, a metabotropic receptor that signals via Gq. To understand the function of this choroid plexus-derived insulin, here we describe a way to genetically target epithelial cells of the choroid plexus using a viral vector. With this, we modulated insulin expression and evaluated behavior. Insulin overexpression in the choroid plexus of wild type mice led to an inhibition in feeding, whereas insulin knockdown in choroid plexus of Ins1-/-Ins2fl/fl mice promoted discrete increases in food intake, especially after a period of fasting. Insulin overexpression in choroid plexus induced roust transcriptomic changes in the hypothalamus, most of which related to axonal growth and synapse-related processes. Finally, activation of Gq signaling in insulin-overexpressing choroid plexuses led to acute AKT phosphorylation in neurons of the arcuate nucleus, suggesting a direct action, through the CSF, of choroid plexus-derived insulin on the hypothalamus. Taken together our findings prove that the choroid plexus is a relevant source of insulin in the central nervous system, with physiological implications in feeding behavior. We believe that choroid plexus-derived insulin has to be taken into consideration in future work pertaining insulin actions in the brain.
Project description:To examine the cellular and transcriptional heterogeneity of choroid plexus tumors we determined the single nucleus transcriptomes of 23,906 nuclei from normal choroid plexus and choroid plexus tumors. The resulting cellular atlas profiles cellular and transcriptional heterogeneity, copy number alterations, and cell-cell interaction networks in normal and cancerous choroid plexus. We observe changes in choroid plexus tumor epithelial cell gene transcription that correlate with genome wide methylation profiles. In addition, we characterize tumor-grade-specific tumor microenvironments that include altered macrophage and mesenchymal cell states, as well as changes in extracellular matrix components.
Project description:Transcriptomic profile of rat choroid plexus (whole tissue) of both male and female sex, epithelial cells captured by fluorescence-activated cell sorting (FACS), and compared to proximal tubules of the kidneys. The transcriptomic profile of choroid plexus displays high similarity between sex and choroid plexus epithelial cells, and lesser similarity to another secretory epithelium, the proximal tubules. The analysis provides an insight into transport mechanisms that could participate in CSF secretion and suggest regulatory candidates.