Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in mice

ABSTRACT: The tumor suppressor CREBBP (CREB binding protein) and the MYCN proto-oncogene are critically involved in brain development. Both genes are frequently mutated in the same tumor entities, including high-grade glioma and medulloblastoma. Therefore, we hypothesized that alterations in both genes cooperate to induce brain tumor formation. For further investigation, hGFAP-cre::CrebbpFl/Fl::lsl-MYCN mice were generated, which combine a Crebbp deletion with an overexpression of MYCN in neural stem cells (NSCs). Within eight months, these animals developed aggressive forebrain tumors that resulted in tumor-related death with a penetrance of 75 percent. The earliest tumors were detectable in the olfactory bulbs of seven-day-old mice. In order to examine the cellular biology of these tumors, single-cell RNA sequencing (scRNA-seq) was performed, which revealed high intratumoral heterogeneity. Data comparison with reference CNS cell types indicated the highest similarity of tumor cells with transit-amplifying or activated NSCs of the ventricular-subventricular zone (V-SVZ). Consequently, we analyzed V-SVZ NSCs of our mouse model with the aim of confirming that the tumors originate from this stem cell niche. Mutant V-SVZ NSCs showed significantly increased cell viability and proliferation as well as reduced glial and neural differentiation in vitro compared to control cells. In summary, we demonstrate the oncogenic potential of a combined loss of function of CREBBP and overexpression of MYCN in this cell population. This mouse model thus provides a valuable tool to study tumor-driving mechanisms in a key neural stem/progenitor cell niche.

ORGANISM(S): Mus musculus

PROVIDER: GSE214983 | GEO | 2023/07/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Single-Cell Transcriptomics and Fate Mapping of Ependymal Cells Reveals an Absence of Neural Stem Cell Function

Project description:Ependymal cells are multi-ciliated cells that form the brain’s ventricular epithelium and a niche for neural stem cells (NSCs) in the ventricular-subventricular zone (V-SVZ). In addition, ependymal cells are suggested to be latent NSCs with a capacity to acquire neurogenic function. This remains highly controversial due to a lack of prospective in vivo labeling techniques that can effectively distinguish ependymal cells from neighboring V-SVZ NSCs. We describe a transgenic system that allows for targeted labeling of ependymal cells within the V-SVZ. Single-cell RNA-seq revealed that ependymal cells are enriched for cilia-related genes and share several stem-cell-associated genes with neural stem or progenitors. Under in vivo and in vitro neural-stem- or progenitor-stimulating environments, ependymal cells failed to demonstrate any suggestion of latent neural-stem-cell function. These findings suggest remarkable stability of ependymal cell function and provide fundamental insights into the molecular signature of the V-SVZ niche.

2018-05-02 | GSE100320 | GEO

Dnmt3a-dependent non-promoter DNA methylation facilitates transcription of neurogenic genes

Project description:This SuperSeries is composed of the following subset Series: GSE22473: Murine postnatal subventricular zone (SVZ) neural stem cells (NSCs): Wild-type (WT) vs. Dnmt3a-null (KO) GSE22474: Genome-wide location analysis of Dnmt3a-mediated epigenetic regulation in murine postnatal subventricular zone (SVZ) neural stem cells (NSCs) [Agilent] GSE22475: Genome-wide location analysis of Dnmt3a-mediated epigenetic regulation in murine postnatal subventricular zone (SVZ) neural stem cells (NSCs) [NimbleGen] Refer to individual Series

2010-06-24 | E-GEOD-22476 | biostudies-arrayexpress

Ependyma-expressed CCN1 restricts the size of the neural stem cell pool in the adult ventricular-subventricular zone

Project description:Adult neural stem cells (NSCs) reside in specialized niches, which hold a balanced number of NSCs, their progeny, and other cells. How niche capacity is regulated to contain a specific number of NSCs remains unclear. Here, we show that ependyma-derived matricellular protein CCN1 (cellular communication network factor 1) negatively regulates niche capacity and NSC number in the adult ventricular-subventricular zone (V-SVZ). Adult ependyma-specific deletion of Ccn1 transiently enhanced NSC proliferation and reduced neuronal differentiation in mice, increasing the numbers of NSCs and NSC units. Although proliferation of NSCs and neurogenesis seen in Ccn1 knockout mice eventually returned to normal, the expanded NSC pool was maintained in the V-SVZ until old age. Inhibition of EGFR signaling prevented expansion of the NSC population observed in CCN1 deficient mice. Thus, ependyma-derived CCN1 restricts NSC expansion in the adult brain to maintain the proper niche capacity of the V-SVZ.

2020-02-19 | GSE137852 | GEO

Transcriptome analysis of medulloblastoma tumors in mice

Project description:The proto-oncogene MYCN is mis-expressed in various types of human brain tumors. To clarify how developmental and regional differences influence transformation, we transduced wild-type or mutationally-stabilized murine N-mycT58A into neural stem cells (NSCs) from perinatal murine cerebellum, brain stem and forebrain. Transplantation of Nmyc WT NSCs was insufficient for tumor formation. N-mycT58A cerebellar and brain stem NSCs generated medulloblastoma/primitive neuroectodermal tumors, whereas forebrain NSCs developed diffuse glioma. Expression analyses distinguished tumors generated from these different regions, with tumors from embryonic versus postnatal cerebellar NSCs demonstrating SHH-dependence and SHH-independence, respectively. These differences were regulated in-part by the transcription factor SOX9, activated in the SHH subclass of human medulloblastoma. Our results demonstrate context-dependent transformation of NSCs in response to a common oncogenic signal. 9 (total) orthotopic tumors generated from E16C, P0C, and P0F NSCs transduced with a mutation-stabilized N-Myc were compared to transduced (but not transplanted) NSCs, NSCs transduced with GFP, and cells derived from the orthotopic tumors. These were also compared to 5 normal P7 cerebella, and 32 medulloblastoma tumors from the GTML mouse model. A cell line derived from a tumor from the GTML mouse model is also included in the comparison.

2012-03-20 | E-GEOD-36594 | biostudies-arrayexpress

Dual and separable roles for Ezh2 in neurogenic astroglia

Project description:The epigenetic mechanisms that enable specialized astrocytes to retain neurogenic competence throughout adult life are still poorly understood. Here we show that astrocytes that serve as neural stem cells (NSCs) in the adult mouse subventricular zone (SVZ) express the histone methyltransferase EZH2. This Polycomb repressive factor is required for neurogenesis independent of its role in SVZ NSC proliferation, as Ink4a/Arf-deficiency in Ezh2-deleted SVZ NSCs rescues cell proliferation, but neurogenesis remains defective. Olig2 is a direct target of EZH2, and repression of this bHLH transcription factor is critical for neuronal differentiation. Furthermore, Ezh2 prevents the inappropriate activation of genes that specify non-SVZ neuronal subtypes. In the human brain, SVZ cells including local astroglia also express EZH2, correlating with postnatal neurogenesis. Thus, EZH2 is an epigenetic regulator that distinguishes neurogenic SVZ astrocytes, orchestrating distinct and separable aspects of adult stem cell biology, which has important implications for regenerative medicine and oncogenesis. Examination of histone modifications (H3K27me3 and H3K4me3) in subventricular zone neural stem cells

2014-05-02 | E-GEOD-56394 | biostudies-arrayexpress

RNA-seq of wild-type and transformed Ink4a/Arf-/-; EGFRvIII neural stem cells in separate or co-culture conditions

Project description:There is increasing evidence demonstrating that adult neural stem cells (NSCs) are the cell of origin of glioblastoma (GBM), the most aggressive subtype of malignant glioma. The earliest stages of hyperplasia are challenging to explore, but likely involve a cross-talk between normal and transformed NSCs. How normal cells respond to this cross-talk and what impact this has on the NSC activation/quiescence balance is poorly understood. We sought to address this question by analysing how transformed and wild-type NSCs isolated from the mouse stem cell niche in the subventricular zone (SVZ) interact. Wild-type and Ink4a/Arf-/-; EGFRvIII transformed NSCs were cultured either separately or in a 50:50 co-culture in serum-free adherent conditions. We observed that the growth of wild-type NSCs was dramatically reduced in the presence of the transformed NSCs. To explore this finding further we performed RNA-seq on NSCs that had been sorted by FACS following five days of culture either separately or in the co-culture condition. This allowed us to identify differentially expressed genes between the different culture conditions.

2020-10-12 | E-MTAB-8580 | biostudies-arrayexpress

Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis

Project description:Neural stem cells (NSCs) generate new neurons throughout life in two distinct areas of the mammalian brain: the subventricular zone (SVZ) lining the lateral ventricles and the hippocampal dentate gyrus (DG). How gene expression signatures differ among NSCs and immature neurons within and between these adult neurogenic regions is unknown. We isolated NSCs and their progeny using transgenic mice expressing GFP under the control of the Sox2 promoter (labeling NSCs) and transgenic mice expressing DsRed under the control of the doublecortin (Dcx) promoter (labeling immature neurons). Comparison of the transcriptomes of SOX2+ cells derived from both neurogenic areas revealed that NSCs are highly similar but that functionally significant differences in gene expression exist: IGF2, which is expressed only in SOX2+ cells in the DG but not in the SVZ, is required for proliferation of DG-derived but not SVZ-derived NSCs. Gene expression profiles strongly diverged in immature neurons, and we provide evidence that ephrinB3, which was up-regulated only in the DG but not in the SVZ during neuronal differentiation, regulates the survival of newborn granule cells. Thus, the data provided here show that stem cell populations in the adult DG and SVZ are similar but have unique properties that manifest themselves later during neural differentiation, resulting in distinct neuronal populations Hippocampi and SVZ from 6 week old DCX-DsRed and Sox2-GFP Reporter mice were dissected and cell sorted using FACS. cDNA were generated and analysed using Agilent Platform.

2011-12-31 | E-GEOD-21208 | biostudies-arrayexpress

Myelin-allied gene expression profile of adult neural progenitors shortly after onset of differentiation

Project description:Spontaneous neural repair from endogenous neural stem cells (NSCs) occurs in response to central nervous system (CNS) injuries or diseases to only a limited extent from endogenous NSCs niches. Uncovering the mechanisms that control neural repair and can be further manipulated to promote towards oligodendrocyte progenitors cells (OPCs) and myelinating oligodendrocytes is a major objective. Our aim was to identify myelin specific transcriptional regulators amongst large transcriptional changes shortly after differentiation of neural stem cells from the subventricular zone (SVZ) of adult mice SVZ-NSCs from adult mice were differentiated for 12 and 24 h in absence of growth factor (bFGF, EGF) and subjected for gene array as compared with undifferentiated NSCs cultured in presence of growth factors (n=5 samples per condition).

2016-06-01 | E-GEOD-76968 | biostudies-arrayexpress

LRIG1 is a gatekeeper to exit from quiescence in adult neural stem cells

Project description:Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signalling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of Lrig1 in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence.

2021-03-18 | GSE168189 | GEO

Transcriptome analysis of medulloblastoma tumors in mice

2012-03-20 | GSE36594 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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