A druggable signaling hub of choroid plexus immune-secretory function
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE192946 | GEO | 2023/02/17
REPOSITORIES: GEO
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Project description:Integrated multi-omics investigation of novel rat models of acquired hydrocephalus, Blood or bacteria in CSF trigger similar choroid plexus (ChP) immune-secretory responses, Crosstalk between ChP immune and epithelial cells drives CSF hypersecretion and ventriculomegaly, Repurposed systemic immunomodulators ameliorate acquired hydrocephalus, Identification of a druggable hub of ChP function relevant for multiple neurological diseases.
2023-02-17 | GSE218143 | GEO
Project description:The choroid plexus (ChP) secretes a half-liter of cerebrospinal fluid (CSF) per day into the cerebral ventricular system and gates immune cell entry into the brain as the blood-CSF barrier. Acquired hydrocephalus, characterized by ventriculomegaly from CSF accumulation, is caused by both brain infection or hemorrhage and is treated by neurosurgical CSF diversion with attendant morbidity and long-term disability. We interrogated novel rat models of post-infectious (PIH) and post-hemorrhagic hydrocephalus (PHH) using a multi-omics, systems biology platform to elucidate mechanisms of disease. Integrated analysis of new genome-level transcriptomic and proteomic ChP datasets demonstrated that lipopolysaccharide in PIH, and blood breakdown products in PHH, trigger highly similar toll-like receptor-4 (TLR4)-dependent immune responses at the ChP-CSF interface. This includes the production of a CSF “cytokine storm” elicited from activated peripherally-derived and border-associated macrophages that accumulate at the ChP. Pro-inflammatory CSF signals stimulate their cognate receptors on ChP epithelial cells in paracrine manner to acutely increase CSF secretion rate via the TNF receptor associated SPAK kinase, which binds and activates a multi-ion transporter and channel complex at the ChP apical membrane. Genetic and pharmacological immunosuppression with repurposed drugs antagonizes SPAK-dependent CSF hypersecretion and prevents acute PIH and PHH. These data expand our understanding of ChP immune-epithelial cell crosstalk, reframe PIH and PHH as related inflammatory disorders vulnerable to systemic immunomodulation, and identify a druggable hub of ChP immune-secretory function that holds promise for other neurological disorders.
2023-02-20 | PXD030678 | Pride
Project description:A subset of infants and adults with hemorrhagic stroke and intraventricular hemorrhage (IVH) ultimately develop a life-threatening accumulation of cerebrospinal fluid (CSF), termed post-hemorrhagic hydrocephalus (PHH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. We describe an adeno-associated viral (AAV) gene augmentation approach leveraging the Na-K-Cl cotransporter, NKCC1, to enhance a choroid plexus (ChP) mechanism of CSF surveillance, potassium homeostasis, and water movement to drive decreases in ventricle size in embryonic, neonatal, and adult mouse models of IVH. Intraventricular blood led to increased CSF [K+], triggered cytosolic calcium in ChP epithelial cells, and was followed by NKCC1 activation. ChP-targeted AAV-NKCC1 rapidly reversed blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity, validating the model and treating the most salient clinical features of PHH. NKCC1 is a bi-directional cotransporter, and these data demonstrate that NKCC1 activation triggered a trans-choroidal, NKCC1-dependent CSF ion/water clearance out of the ventricle. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to mitigate ventriculomegaly, indicating that the beneficial effects of NKCC1 augmentation required both elevated CSF [K+] and upstream activation via phosphorylation. Excessive CSF [K+] fluctuations correlated with permanent shunting outcome in humans following hemorrhagic stroke, suggesting potential therapeutic benefits. Collectively, these data highlight a novel role for the ChP in rapid compensation for alterations in CSF homeostasis following IVH and demonstrate the utility of targeted gene therapy to mitigate intracranial fluid accumulation following hemorrhage.
2024-05-24 | PXD039738 | Pride
Project description:3 mice per timepoint (9am and 9pm) with FoxJ1-Cre x TRAP-BAC-EGFP:L10a dissected choroid plexus. Transmission and secretion of signals via the choroid plexus (ChP) brain barrier can modulate brain states via regulation of cerebrospinal fluid (CSF) composition. Here, we developed a platform to analyze diurnal variations in male mouse ChP and CSF. Ribosome profiling of ChP epithelial cells revealed diurnal translatome differences in metabolic machinery, secreted proteins, and barrier components. Using ChP and CSF metabolomics and blood-CSF barrier analyses, we observed diurnal changes in metabolites and cellular junctions. We then focused on transthyretin (TTR), a diurnally regulated thyroid hormone chaperone secreted by the ChP. Diurnal variation in ChP TTR depended on Bmal1 clock gene expression. We achieved real-time tracking of CSF-TTR in awake TtrmNeonGreen mice via multi-day intracerebroventricular fiber photometry. Diurnal changes in ChP and CSF TTR levels correlated with CSF thyroid hormone levels. These datasets highlight an integrated platform for investigating diurnal control of brain states by the ChP and CSF.
2023-05-10 | GSE161877 | GEO
Project description:The choroid plexuses (ChPs) are the main regulators of cerebrospinal fluid (CSF) composition and thereby also control the composition of a principal source of signaling molecules that is in direct contact with neural stem cells in the developing brain. The regulators of ChP development mediating the acquisition of a fate that differs from the neighboring neuroepithelial cells are poorly understood. Here, we demonstrate in mice a crucial role for the transcription factor Otx2 in the development and maintenance of ChP cells. Deletion of Otx2 by the Otx2-CreERT2 driver line at E9 resulted in a lack of all ChPs, whereas deletion by the Gdf7-Cre driver line affected predominately the hindbrain ChP, which was reduced in size, primarily owing to an increase in apoptosis upon Otx2 deletion. Strikingly, Otx2 was still required for the maintenance of hindbrain ChP cells at later stages when Otx2 deletion was induced at E15, demonstrating a central role of Otx2 in ChP development and maintenance. Moreover, the predominant defects in the hindbrain ChP mediated by Gdf7-Cre deletion of Otx2 revealed its key role in regulating early CSF composition, which was altered in protein content, including the levels of Wnt4 and the Wnt modulator Tgm2. Accordingly, proliferation and Wnt signaling levels were increased in the distant cerebral cortex, suggesting a role of the hindbrain ChP in regulating CSF composition, including key signaling molecules. Thus, Otx2 acts as a master regulator of ChP development, thereby influencing one of the principal sources of signaling in the developing brain, the CSF. We performed gene expression microarray analysis of fourth ventricular choroid plexus tissue from Otx2 k.o. mice compared to wildtype mice from the same litters.
2013-02-05 | E-GEOD-27630 | biostudies-arrayexpress
Project description:The choroid plexuses (ChPs) are the main regulators of cerebrospinal fluid (CSF) composition and thereby also control the composition of a principal source of signaling molecules that is in direct contact with neural stem cells in the developing brain. The regulators of ChP development mediating the acquisition of a fate that differs from the neighboring neuroepithelial cells are poorly understood. Here, we demonstrate in mice a crucial role for the transcription factor Otx2 in the development and maintenance of ChP cells. Deletion of Otx2 by the Otx2-CreERT2 driver line at E9 resulted in a lack of all ChPs, whereas deletion by the Gdf7-Cre driver line affected predominately the hindbrain ChP, which was reduced in size, primarily owing to an increase in apoptosis upon Otx2 deletion. Strikingly, Otx2 was still required for the maintenance of hindbrain ChP cells at later stages when Otx2 deletion was induced at E15, demonstrating a central role of Otx2 in ChP development and maintenance. Moreover, the predominant defects in the hindbrain ChP mediated by Gdf7-Cre deletion of Otx2 revealed its key role in regulating early CSF composition, which was altered in protein content, including the levels of Wnt4 and the Wnt modulator Tgm2. Accordingly, proliferation and Wnt signaling levels were increased in the distant cerebral cortex, suggesting a role of the hindbrain ChP in regulating CSF composition, including key signaling molecules. Thus, Otx2 acts as a master regulator of ChP development, thereby influencing one of the principal sources of signaling in the developing brain, the CSF.
2013-02-05 | GSE27630 | GEO
Project description:Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer’s disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relation between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans. We used an APP knock-in mouse model, APPNL-G-F, exhibiting amyloid pathology, to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF using liquid chromatography mass spectrometry. Mouse proteomes were investigated at the age of 7 weeks (n=5) and 40 weeks (n=5). Results were compared with existing human AD CSF proteomic data (n=496) to identify key proteins and pathways associated with ChP changes in AD.
2024-08-10 | PXD052590 | Pride
Project description:Age-appropriate regulation of cerebrospinal fluid (CSF) dynamics including production, flow, and clearance (e.g. via glymphatics and dural lymphatics) is essential for brain health. The choroid plexus (ChP) is an important compartment in CSF dynamics but its contribution is poorly understood. To identify temporally regulated ChP epithelial cell functions that may relate to increased ATP demand, we investigated transcripts that are prioritized for translation, therefore reflecting the functional preference of the ChP tissue. We employed Translating Ribosomal Affinity Purification. We identified ChP Na-K-Cl co-transporter [NKCC1] as developmentally regulated, in both expression and function, by mechanisms ranging from epigenetic (NuRD) to post-translational, coupled with increased ATP production. Premature NKCC1 overexpression in ChP accelerated CSF [K+] reduction, reduced ventricle size, and increased intracranial compliance by adulthood as measured by a murine intracranial pressu re monitor paired serially with MRI. Our data point to a critical developmental period when ChP transiently absorbs CSF through NKCC1-mediated K+ transport, which bears implications on lifelong brain fluid homeostasis and health.
2020-11-28 | GSE138970 | GEO
Project description:The choroid plexus (ChP) is a protective epithelial barrier that filters blood and secretes cerebrospinal fluid (CSF), an important fluid for nutrient maintenance in the brain and transport of signalling molecules. Here, we establish human ChP organoids with a selective epithelial barrier that secrete CSF-like fluid in self-contained compartments. We show that this in vitro barrier exhibits the same selectivity to small molecules as the in vivo counterpart, and that ChP-CSF organoids can predict CNS permeability of novel compounds. Characterization of the transcriptomic signature of ChP organoids and the proteomic make-up of the CSF-like fluid demonstrate a high degree of similarity to the in vivo counterpart. We leverage the fact that these organoids represent the tissue in isolation to examine their cellular make-up, and explore the specialized epithelial subtypes involved in de novo production of key CSF components. This reveals the presence of heterogeneous epithelial ChP populations, including a newly identified myoepithelial cell type, and uncovers human-specific factors secreted by these specialized cell types.
2020-06-11 | GSE150903 | GEO
Project description:Add1 Null mice on the C57BL/6J background develop hydrocephalus that may be due to gene expression changes in the choroid plexus. We used microarrays to detail choroid plexi gene expression prior to the manifestation of hydrocephalus. Choroid plexi from the four ventricle were dissected out, for RNA extraction and hybridization to Affymetrix microarrays, from male Add1 wildtype, heterozygous and null mice at three weeks of age. Five mice were selected for each genotype to assess gene expression prior to the development of hydrocephalus.
2012-04-08 | E-GEOD-37098 | biostudies-arrayexpress