Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Gene expression changes caused by YAP overexpression and Nf2 deletion in the developing mouse brain

ABSTRACT: The transcriptional coactivator YAP is the key downstream effector of the Hippo pathway. YAP overexpression in the developing mouse brain results in excessive expansion of the neural progenitor pool and severe perturbation of brain development. Nf2/Merlin is a tumor suppressor whose mutations are found in many human cancers. Loss of Merlin during brain development causes overexpansion of the neural progenitor pool. We used microarrays to identify the gene expression changes caused by YAP overexpression and Nf2 deletion.

ORGANISM(S): Mus musculus

PROVIDER: GSE48078 | GEO | 2013/06/19

SECONDARY ACCESSION(S): PRJNA208861

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Gene expression changes caused by YAP overexpression and Nf2 deletion in the developing mouse brain

Project description:The transcriptional coactivator YAP is the key downstream effector of the Hippo pathway. YAP overexpression in the developing mouse brain results in excessive expansion of the neural progenitor pool and severe perturbation of brain development. Nf2/Merlin is a tumor suppressor whose mutations are found in many human cancers. Loss of Merlin during brain development causes overexpansion of the neural progenitor pool. We used microarrays to identify the gene expression changes caused by YAP overexpression and Nf2 deletion. We used a double-transgenic system to overexpress YAP in the developing mouse brain by crossing mice carrying a doxycycline-dependent allele of YAP1-S127A (TetO-YAP1) with those expressing the reverse tetracycline-dependent transactivator rtTA under the control of the neural progenitor-specific Nestin promoter (Nes-rtTA) and feeding the dam with doxycycline-containing food (200 mg/kg) from E7.5. We conditionally deleted Nf2 using the telencephalon-specific Emx1-Cre.

2013-06-19 | E-GEOD-48078 | biostudies-arrayexpress

RNA sequencing of endothelial cells from mouse brain of WT and EC-specific Nf2-deleted mice

Project description:Understanding of transciptome changes of endothelial cells (ECs) in mouse brain by Nf2/Merlin is unknown. Here, we performed bulk RNA sequencing to investigate the changes of expression patterns by Nf2/Merlin deletion in mouse brain ECs

2022-03-24 | GSE186189 | GEO

Analysis of the transcriptomic profile of WT mouse embryonic fibroblast (MEF WT) and Nf2-knockout mouse embryonic fibroblast (MEF Nf2 KO) cell lines

Project description:Merlin is the tumor suppressor protein encoded by the NF2 gene. The expression of Merlin is remarkably decreased in metastatic breast cancer tissues irrespective of the breast cancer subtype. In order to ascribe clinical relevance, we re-capitulated the loss of Merlin in breast cancer cells. Merlin deficiency elicited a markedly invasive phenotype. In order to overcome the challenge of embryonic lethality of a total Nf2-knockout, we generated a unique mammary-specific Nf2-knockout mouse mammary tumor model. Both, the Nf2-knockout mouse embryonic fibroblasts (MEF) and Merlin-deficient breast tumor cells displayed a robust invasive phenotype. Transcriptomic assessment of Nf2-knockout MEFs revealed notable alterations in glutathione transferase and antioxidant networks indicating a role for Merlin in redox biology. This programmatic alteration resonated with the pathways that emerged from breast tumor cells engineered for Merlin deficiency.

2021-04-14 | GSE157677 | GEO

YAP/TAZ inhibition induces metabolic and signaling rewiring resulting in new targetable vulnerabilities in NF2-deficient tumor cells

Project description:The NF2 gene, which encodes the Merlin protein, is a bona fide tumor suppressor whose mutations underlie inherited tumor syndrome Neurofibromatosis Type 2 (NF2). Recent large-scale genome sequencing studies have also identified NF2 as one of the most frequently mutated genes in VHL-wild-type kidney cancers. Even though a wide array of downstream signaling pathways has been described for Merlin/NF2, the molecular mechanisms underpinning the growth and survival of NF2 mutant tumors remain poorly understood. Using an inducible orthotopic kidney tumor model, we demonstrate for the first time that silencing of YAP/TAZ is sufficient to induce regression of pre-established NF2 deficient kidney tumors. Mechanistically, we show that YAP/TAZ ablation severely diminishes glycolysis by downregulating the transcription of several glycolytic enzymes and growth factors and RTK-PI3K-AKT signaling, resulting in growth arrest. On the other hand, YAP/TAZ depletion significantly increases mitochondrial respiration and overproduction of mitochondrial ROS, resulting in redox imbalance and oxidative stress cell death when challenged by nutrient stress. Furthermore, we identify lysosome-mediated cAMP-PKA/EPACdependent activation of the RAF-MEK-ERK pathway to be a novel resistance mechanism that allows NF2 deficient tumor cells to survive YAP/TAZ inhibition in vitro and in vivo. Finally, unbiased analysis of TCGA primary kidney tumor transcriptomes confirms strong correlations of a YAP/TAZ signature with the expression of glycolysis, oxidative phosphorylation and lysosomal genes, validating the clinical relevance of our findings.

2019-05-04 | GSE125408 | GEO

Proteomic analysis of the NF2/Merlin Interactome by Proximity Biotinylation

Project description:Neurofibromatosis type 2 is an inherited neoplastic disease consisting of schwannomas, meningiomas, and ependymomas that is caused by inactivation of the tumor suppressor gene NF2. The NF2 gene product, merlin, has no intrinsic catalytic activity; its tumor suppressor function is mediated through the proteins with which it interacts. However, there is no consensus about which merlin interactions are necessary for tumor suppression. We used proximity biotinylation followed by mass spectrometry and direct binding assays to characterize the proteins that associate with merlin and merlin mutants in immortalized Schwann cells. We identified 52 proteins that associate with merlin, including a previously unreported merlin binding protein, ASPP2. Our results identify merlin as a component of mechanosensing signal transduction pathways in cell junctions, in the context of a specific set of structures and molecules through which it acts, in a cell type relevant to schwannoma formation.

2019-04-25 | PXD012017 | Pride

Merlin/NF2-loss Driven Tumorigenesis Linked to CRL4(DCAF1)-Mediated Inhibition of the Hippo Pathway Components Lats1 and 2

Project description:Studies in drosophila have suggested that Merlin/NF2 suppresses tumorigenesis by activating upstream components of the Hippo pathway at or near the plasma membrane. In contrast, studies of Merlin-deficient tumor cells have indicated that Merlin suppresses tumorigenesis by entering into the nucleus where it inhibits the E3 ubiquitin ligase CRL4DCAF1. We found that CRL4DCAF1 promotes YAP and TEAD-dependent transcription by ubiquitylating and thereby inhibiting Lats1 and 2 in the nucleus. Genetic epistasis experiments and analysis of tumor-derived missense mutations indicate that this signaling connection sustains the oncogenicity of Merlin-deficient tumor cells. Analysis of clinical samples confirms that this pathway operates in NF2 mutant mesotheliomas, schwannomas and meningiomas. We conclude that de-repressed CRL4DCAF1 controls the output of the Hippo pathway by inhibiting Lats1 and 2 in the nucleus.

2014-07-15 | GSE56157 | GEO

Merlin/NF2 Suppresses Tumorigenesis by Inhibiting the E3 Ubiquitin Ligase CRL4DCAF1 in the Nucleus

Project description:Current models imply that the FERM domain protein Merlin, encoded by the tumor suppressor NF2, inhibits mitogenic signaling at or near the plasma membrane. Here, we show that the closed, growth inhibitory form of Merlin accumulates in the nucleus, binds to the E3 ubiquitin ligase CRL4DCAF1, and suppresses its activity. Depletion of DCAF1 blocks the promitogenic effect of inactivation of Merlin. Conversely, enforced expression of a Merlin-insensitive mutant of DCAF1 counteracts the antimitogenic effect of Merlin. Re-expression of Merlin and silencing of DCAF1 induce a similar, tumor-suppressive program of gene expression. Tumor-derived mutations invariably disrupt Merlinâs ability to interact with or inhibit CRL4DCAF1. Finally, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. We propose that Merlin suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4DCAF1. To examine if Merlin controls gene expression through inhibition of CRL4DCAF1, and define the general function of this ligase, we compared the gene expression program activated by expression of Merlin or by depletion of DCAF1 in Merlin-null FC-1801 mouse Schwannoma cells

2010-03-09 | E-GEOD-19305 | biostudies-arrayexpress

Genome-Wide CRISPR Screen Identifies an NF2-adheren junction mechanistic dependency for cardiac lineage

Project description:Cardiac differentiation involves a stepwise clearance of repressors and fate-restricting regulators through the modulation of BMP/Wnt-signaling pathways. However, the mechanisms and how regulatory roadblocks are removed with specific developmental signaling pathways remain unclear. Here, we performed a genome-wide CRISPR screen to uncover essential regulators of cardiomyocyte specification in human embryonic stem cells (hESCs) and identify NF2, a Moesin-Ezrin-Radixin Like (MERLIN) Tumor Suppressor, as an upstream driver of cardiomyocyte specification. Transcriptional regulation and trajectory inference from NF2-null cells reveal the loss of cardiomyocyte identity and the acquisition of non-mesodermal identity. Sustained elevation of early mesoderm lineage repressor SOX2 and upregulation of late anti-cardiac regulators CDX2, MSX1 in NF2 knockout cells reflect a necessary role for NF2 in removing regulatory roadblocks. Since YAP is a known repressor of mesendoderm genes, we found that NF2 and AMOT cooperatively bind to YAP during mesendoderm formation, thereby preventing YAP activation independent on canonical MST-LATS1 kinase activity. Mechanistically, cardiomyocyte lineage identity was rescued by wild-type and NF2 Serine-518 phospho-mutants, but not NF2 FERM-domain blue-box mutants, showing that the critical FERM domain-dependent formation of the AMOT-NF2-YAP scaffold complex at the adherens junction is required for cardiomyocyte lineage differentiation. These results provide mechanistic insight into the essential role of NF2 for cardiomyocyte lineage specification by sequestering the repressive effect of YAP and relieving regulatory roadblocks en route to cardiomyocytes.

2024-04-30 | GSE244362 | GEO

High-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling.

Project description:Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset is of higher grade, recurs even after multiple surgeries, and frequently fatal. Around half of meningiomas harbor inactivating mutations in NF2. While low-grade NF2 mutant meningiomas harbor few additional mutations in addition to NF2 inactivation, high-grade NF2 mutant tumors frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as an oncogene in NF2 mutant meningiomas. Here, we show that high-grade NF2 mutant meningiomas downregulate YAP1 signaling, in part through upregulating the expression of the YAP1 competitor VGLL4 and the YAP1 upstream regulators FAT3/4. Overexpression of VGLL4 resulted in the downregulation of YAP activity and the growth inhibition of low-grade NF2 mutant meningioma cells. Our results have important implications for the efficacy of therapies targeting oncogenic YAP1 in high-grade NF2 mutant meningiomas.

2024-08-26 | GSE263122 | GEO

Transcriptome changes of endothelial cells in mouse tumor by Nf2/Merlin

Project description:To investigate the trancriptomic changes of endothelial cells (ECs) by Nf2/Merlin, Lewis Lung Carcinoma (LLC) tumor ECs from Ctrl and NF2 KO mice were sorted by FACS and single-cell RNA seq was performed.

2021-10-21 | GSE186162 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data