Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1312981 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The intrinsic drivers of migration in glioblastoma (GBM) are poorly understood. To better capture the native molecular imprint of GBM and its developmental context, we isolate human stem cell populations from GBM (GSC) and germinal matrix tissues and map their chromatin accessibility via ATAC-seq. We uncover two distinct regulatory GSC signatures, a developmentally-shared/proliferative and a tumor-specific/migratory one in which TEAD1/4 motifs are uniquely overrepresented. Using ChIP-PCR we validate TEAD1 trans occupancy at accessibility sites within EGFR, AQP4, and CDH4. To further characterize TEAD’s functional role in GBM, we knockout TEAD1 or TEAD4 in patient-derived GBM lines using CRISPR-Cas9. TEAD1 ablation robustly diminishes migration, both in vitro and in vivo, and alters migratory and EMT transcriptome signatures with consistent downregulation of its target AQP4. TEAD1 overexpression restores AQP4 expression, and both TEAD1 and AQP4 overexpression rescue migratory deficits in TEAD1-knockout cells, implicating a direct regulatory role for TEAD1-AQP4 in GBM migration.
2018-07-27 | GSE117685 | GEO
Project description:Aquaporin-4 (AQP4) is highly polarized to perivascular astrocytic endfeet. Loss of AQP4 polarization is associated with many diseases. In Alzheimer's disease (AD), it is found that AQP4 loos its normal location and thus reduce the clearance of amyloid-β plaques and Tau protein. Clinical and experimental studies show that moxibustion can improve the learning and memory abilities of AD. In order to explore whether moxibustion can affect the polarization of AQP4 around blood brain barrier (BBB), we used spatial transcriptomics (ST) to analyze the expression and polarization of Aqp4 in wild type mice, APP/PS1 mice and APP/PS1 mice intervened by moxibustion. The results showed that moxibustion improved the loss of abnormal polarization of AQP4 in APP/PS1 mice, especially in the hypothalamic BBB. Besides, there are other 31 genes with Aqp4 as the core have the similar depolarization in APP/PS1 mice, most of which are also membrane proteins. The majority of them have been reversed by moxibustion. At the same time, we employed the cerebrospinal fluid circulation gene set, which was found being on a higher level in the group of APP/PS1 mice with moxibustion treatment. Finally, in order to further explore its mechanism, we analyzed the mitochondrial respiratory chain complex enzymes closely related to energy metabolism, and found that moxibustion can significantly increase the expression of mitochondrial respiratory chain enzymes such as Cox6a2 in the hypothalamus, which could provide energy for mRNA transport. Our research shows that increasing the polarization of hypothalamic Aqp4 through mitochondrial energy supply may be an important target for moxibustion to improve APP/PS1 mice’s cognitive impairment.
2023-02-22 | GSE222981 | GEO
Project description:Here we use MeRIP-Seq to analyze global adenosine methylation (m6A) in mRNAs in the midbrain and striatum of Fto-deficient mice. We find that Fto deficiency leads to increased methylation within a subset of mRNAs important for neuronal signaling, including many within the dopaminergic signaling pathway. Collectively, our results show that Fto regulates demethylation of specific mRNAs in vivo, and this activity relates to control of dopaminergic transmission. Profiling of m6A in midbrain and striatum from FTO knockout mice
2013-06-15 | E-GEOD-47216 | biostudies-arrayexpress
Project description:Neuromyelitis optica spectrum disorder (NMOSD) is a rare neurological autoimmune disease caused autoantibodies targeting the astrocytic water channel aquaporin-4 (AQP4). Binding to AQP4 initiates the activation of innate immune components, especially the complement system. Both in-vivo and in-vitro models have been developed to study the molecular pathophysiology of NMOSD. The aim of our study was to characterize the molecular response of four human cell lines (AQP4-ECFP expressing U-87MG glioblastoma cells, U-87MG expressing only ECFP, HEK293 cells expressing AQP4-EmGFP and human primary astrocytes) to a treatment with AQP4 antibody E5415A and human complement. Complement-dependent cytotoxicity was induced by this treatment in AQP4-expressing cells by the classical complement pathway. Transcriptomic profiles of the in-vitro U-87MG-AQP4-ECFP model and an in-vivo rat model shared a proinflammatory shift towards NF-κB and interleukin-6 pathways. These findings were confirmed on the mRNA and protein levels and treatment with serum samples from AQP4 antibody seropositive NMOSD patients resulted in a similar response. Additionally, NF-κB upregulation was shown by immunohistochemistry in medulla oblongata lesions of NMOSD patients. In conclusion, interleukin-6 and NF-κB pathways play a key role in inflammation caused by the activation of the classical complement pathway in a human cellular model of NMOSD using U-87MG-AQP4-ECFP cells. Under revision in Scientific Reports, preprint available at: https://www.researchsquare.com/article/rs-7064018/v1
2025-10-01 | GSE291954 | GEO
Project description:The thymus contains some B cells that are located at the corticomedullary junction. We found that these thymic B cells express and present the water channel protein AQP4 and are necessary and sufficient to mediate the negative selection of AQP4-reactive thymocytes. In order to express and present AQP4, thymic B cells need to be licensed through a CD40 signal. Here, we tested the significance of CD40 signaling in thymic B cells for the expression and presentation of distinct autoantigens (besides AQP4) to orchestrate thymocyte selection for these autoantigens.
2023-12-20 | GSE244363 | GEO
Project description:Global gene expression profile of midbrain neural differentiation of mESCs from WT and ERb knockout mice, with or without the selective ERb agonist LY3201 (0.5 nM). Estrogen receptor beta (ERβ) is highly expressed in the fetal brain and is essential for proper corticogenesis during development. Nevertheless, the transcriptional signatures regulated by ERβ during defined neural differentiation stages have not been investigated. In the present study we used mouse embryonic stem cells (mESCs) from wildtype (WT) and ERβ knockout (BERKO) mice to derive neural precursor cells (NPCs) and further differentiated these towards defined midbrain neural fates. This allowed us to systematically investigate transcriptionally active determinants during stages of midbrain neurogenesis. We found that ERβ is important during early neural development in regulating proliferation and maintaining the stem cell pool of neuroepithelial and midbrain stem cells. Detailed gene profiling analysis revealed that loss of ERβ perturbs normal neurogenesis by affecting the expression of factors involved in cell adhesion, axon guidance, and signaling of Notch, Wnt, glutamate- and GABA receptors. Among these we identified several factors that are crucial for dopaminergic neuron development and maintenance, as well as the promotion of oligodendrocyte differentiation. We also demonstrate that these effects are largely independent of ligand activated ERβ. Our data identifies ERβ as an important component in midbrain neurogenesis, where its disruption results in premature depletion of the neural stem cell pool in favor of oligodendrogliogenesis.
2017-10-09 | GSE103312 | GEO
Project description:To investigate the genetic differencesin human AQP4-IgG group and control-IgG group , we established primary astrocytes line. We then performed gene expression profiling analysis using data obtained from RNA-seq after 48h with stimulation with human AQP4-IgG and control-IgG.
2023-04-12 | GSE229365 | GEO
Project description:Individual cell shape and integrity must precisely be orchestrated during morphogenesis. Here, we determine function of type II cadherins, Cdh6, Cdh8, and Cdh11, whose expression combinatorially demarcates the mouse neural plate/tube. While CRISPR/Cas9-based single type II cadherin mutants show no obvious phenotype, Cdh6/8 double knockout mice develop intermingled forebrain/midbrain compartments as these two cadherins’ expression opposes at the nascent boundary. Cdh6/8/11 triple, Cdh6/8 double or Cdh8/11 double knockout mice further cause exencephaly just within the cranial region where mutated cadherins’ expression merges. In the Cdh8/11 double knockout midbrain, we observe less-constricted apical actin meshwork, ventrally-directed spreading, and occasional hyperproliferation among dorsal neuroepithelial cells as origins for exencephaly. These results provide rigid evidence that, by conferring distinct adhesive codes to each cell, redundant type II cadherins serve essential and shared roles in compartmentalization and neurulation, both of which proceed under the robust control of the number, positioning, constriction, and fluidity of neuroepithelial cells.
2020-09-16 | GSE157008 | GEO
Project description:Alpha-synuclein (aSyn) is a central player in the pathogenesis of synucleinopathies due to its accumulation in typical protein aggregates in the brain. However, it is still unclear how it contributes to neurodegeneration. Type-2 diabetes mellitus is a risk factor for Parkinson’s disease (PD) and, interestingly, a common molecular alteration among these disorders is the age-associated increase in protein glycation. We hypothesized that glycation-induced neuronal dysfunction might be a contributing factor in synucleinopathies. Here, we dissected the specific impact of methylglyoxal (MGO, a glycating agent) in mice overexpressing aSyn in the brain. We found that MGO-glycation potentiates motor, cognitive, olfactory, and colonic dysfunction in aSyn transgenic (Thy1-aSyn) mice that received a single dose of MGO via intracerebroventricular (ICV) injection. aSyn accumulates in the midbrain, striatum, and prefrontal cortex, and protein glycation is increased in the cerebellum and midbrain. SWATH mass spectrometry analysis, used to quantify changes in the brain proteome, revealed that MGO mainly increase glutamatergic-associated proteins in the midbrain (NMDA, AMPA, glutaminase, VGLUT and EAAT1), but not in the prefrontal cortex, where it mainly affects the electron transport chain. Notably, the glycated proteins in the midbrain of Thy1-aSyn mice that received MGO strongly correlate with PD and dopaminergic pathways. Overall, we demonstrated that MGO-induced glycation accelerates PD-like sensorimotor and cognitive alterations and suggest that the increase of glutamatergic signaling may underly these events. Our study sheds new light into the enhanced vulnerability of the midbrain in PD-related synaptic dysfunction and suggests that glycation suppressors and anti-glutamatergic drugs may hold promise as disease-modifying therapies for synucleinopathies.
2022-05-20 | PXD032832 | Pride
Project description:Parkinson's disease (PD) is defined by the degeneration of nigral dopaminergic (DA) neurons and can be caused by monogenic mutations of genes such as parkin. The lack of phenotype in parkin knockout mice suggests that human nigral DA neurons have unique vulnerabilities. Here we generate induced pluripotent stem cells from normal subjects and PD patients with parkin mutations. We demonstrate that loss of parkin in human midbrain DA neurons greatly increases the transcription of monoamine oxidases and oxidative stress, significantly reduces DA uptake and increases spontaneous DA release. Lentiviral expression of parkin, but not its PD-linked mutant, rescues these phenotypes. The results suggest that parkin controls dopamine utilization in human midbrain DA neurons by enhancing the precision of DA neurotransmission and suppressing dopamine oxidation. Thus, the study provides novel targets and a physiologically relevant screening platform for disease-modifying therapies of PD.
2012-01-21 | GSE35190 | GEO