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RNAseq of nestin-expressing murine brainstem progenitors infected with ACVR1 WT or R206H ACVR1 with and without H3.1K27M

ABSTRACT: RNAseq of nestin-expressing murine brainstem progenitors infected with ACVR1 WT or R206H ACVR1 with and without H3.1K27M

PROVIDER: PRJNA516939 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8485370_1.fastq.gz	Fastqsanger.gz
	SRR8485370_2.fastq.gz	Fastqsanger.gz
	SRR8485371_1.fastq.gz	Fastqsanger.gz
	SRR8485371_2.fastq.gz	Fastqsanger.gz
	SRR8485362_1.fastq.gz	Fastqsanger.gz

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RNAseq of nestin-expressing murine brainstem progenitors infected with ACVR1 WT or R206H ACVR1 with and without H3.1K27M

Project description:Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, resulting in the death of 200-300 children each year in the United States. Recently it was discovered that approximately 25% of all DIPG cases harbor activating mutations in ACVR1, a gene that encodes Activin A receptor (ALK2), a receptor in the bone morphogenetic protein (BMP) pathway, and that DIPGs with ALK2 mutations commonly harbor an H3.1K27M mutation. Herein, we used the RCAS/TVA retroviral system to study the effects of ACVR1 mutations and H3.1K27M on DIPG pathogenesis. In vitro expression of R206H ACVR1 with and without H3.1K27M in nestin-expressing brainstem progenitors resulted in upregulation of mesenchymal markers and gene set enrichment analysis (GSEA) revealed Stat3 pathway activation. Neonatal expression of ACVR1 R206H or G328V in combination with H3.1K27M and p53 deletion in nestin-expressing brainstem progenitors induced glioma-like lesions expressing mesenchymal markers with Stat3 activation but was not sufficient for full gliomagenesis. In combination with platelet-derived growth factor A (PDGFA) signaling, ACVR1 R206H and H3.1K27M significantly decreased survival and increased tumor incidence. We demonstrate that targeting the BMP signaling pathway may be an effective therapeutic strategy to treat ACVR1 R206H mutant DIPGs. Exogenous Noggin expression at tumor initiation significantly increased tumor latency and treatment of ACVR1 R206H mutant murine DIPGs with LDN212854, an ACVR1 inhibitor, significantly prolonged their survival. We confirm relevance of our model to the human disease as human DIPG models with ACVR1 mutations were also sensitive to treatment with LDN212854 in vitro. Altogether, our studies demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile in part due to Stat3 activation, and identify LDN212854 as a promising compound to treat children with DIPG.

2019-01-25 | GSE125627 | GEO

RNAseq analysis of murine brainstem gliomas with and without H3.3K27M

Project description:Using the RCAS/tv-a system, we induced murine brainstem gliomas (PDGF-B; p53 loss using RCAS-Cre with and without H3.3K27M) in Nestin tv-a; p53 floxed mice

2017-05-11 | GSE98765 | GEO

scRNA-seq time course of cerebellar Nestin-expressing progenitors from neonatal mice with and without injury at birth

Project description:scRNA-seq time course of cerebellar Nestin-expressing progenitors from neonatal mice with and without injury at birth

| PRJEB66207 | ENA

Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas

Project description:Purpose: The purpose of this study was to assess the effect of targeting the Acvr1G328V mutation to oligoendrocyte lineage cells, on gene expression in the brainstem of mice at postnatal day 7 Methods: Total RNA was extracted from the brainstem of postnatal day 7 Acvr1+/+;Olig2Cre/+ and Acvr1floxG328V/+;Olig2Cre/+ littermates, processed using the Illumina TruSeq Stranded Total RNA Sample Preparation kit, and subjected to deep sequencing. Results: A total of 247 genes were differentially expressed between the genotypes, with a corrected p value of less than 0.05. Of these genes, 125 were upregulated while 122 were downregulated. Many of the most downregulated genes were mature oligodendrocyte markers, while several genes that control oligodendrocyte progenitor formation and function were upregulated. Conclusions: The Acvr1G328V mutation causes differentiation arrest of oligodendroglial lineage cells.

2020-02-14 | GSE142776 | GEO

Comparison between Nestin+ and Nestin- Ptch1 deficient GNPs

Project description:The intermediate filament protein Nestin serves as a biomarker for stem cells and has been used to identify subsets of cancer stem-like cells. However, the mechanistic contributions of Nestin to cancer pathogenesis are not understood. Here we report that Nestin binds the hedgehog pathway transcription factor Gli3 to mediate the development of medulloblastomas of the hedgehog subtype. In a mouse model system, Nestin levels increased progressively during medulloblastoma formation resulting in enhanced tumor growth. Conversely, loss of Nestin dramatically inhibited proliferation and promoted differentiation. Mechanistic investigations revealed that the tumor-promoting effects of Nestin were mediated by binding to Gli3, a zinc finger transcription factor that negatively regulates hedgehog signaling. Nestin binding to Gli3 blocked Gli3 phosphorylation and its subsequent proteolytic processing, thereby abrogating its ability to negatively regulate the hedgehog pathway. Our findings show how Nestin drives hedgehog pathway-driven cancers and uncover in Gli3 a therapeutic target to treat these malignancies.

2016-08-09 | GSE84392 | GEO

Comparison between Nestin+ and Nestin- Ptch1 deficient GNPs

2016-08-09 | E-GEOD-84392 | biostudies-arrayexpress

Differential gene expression in mACVR1 NS v wt-ACVR1 NS.

Project description:To study the effect of the ACVR1 G328V mutation in tumor neurospheres with a background of NRASV12 overexpression and p53 knockdown. The goal of this study was to identify differentially expressed genes between mACVR1 NS v wt-ACVR1 NS.

2020-04-16 | GSE148732 | GEO

ACVR1-mutant posterior fossa ependymoma

Project description:ACVR1-mutant posterior fossa ependymoma

| PRJNA802906 | ENA

A population of Nestin-expressing progenitors in the cerebellum exhibits increased tumorigenicity.

Project description:It is generally believed that cerebellar granule neurons originate exclusively from granule neuron precursors (GNPs) in the external germinal layer (EGL). Here we identified a rare population of neuronal progenitors in mouse developing cerebellum that expresses Nestin. Although Nestin is widely considered a marker for multipotent stem cells, these Nestin-expressing progenitors (NEPs) are committed to the granule neuron lineage. Unlike conventional GNPs, which reside in the outer EGL and proliferate extensively, NEPs reside in the deep part of the EGL and are quiescent. Expression profiling revealed that NEPs are distinct from GNPs and, in particular, express markedly reduced levels of genes associated with DNA repair. Consistent with this, upon aberrant activation of Sonic hedgehog (Shh) signaling, NEPs exhibited more severe genomic instability and gave rise to tumors more efficiently than GNPs. These studies revealed a previously unidentified progenitor for cerebellar granule neurons and a cell of origin for medulloblastoma.

| S-EPMC3845444 | biostudies-literature

Undifferentiated mouse embryonic stem cells, differentiated nestin-positive cells and fibroblast feeder layer.

Project description:Embryonic stem (ES) cells and ES cell-derived progeny characterized by nestin expression (including neural progenitors) were studied (three independent experiments). The mouse ES cell line R1 was cultured on a feeder layer of mouse embryonic fibroblasts (FL). ES cells were differentiated into nestin-positive cells for 4+8 days and 4+11 days according to the differentiation protocol by Rolletschek et al. (Mechanisms of Development 105, 93-104, 2001). The study was performed with three independent cell cultures (= triplicates). RNA was prepared from both undifferentiated ES cells and ES cell-derived nestin-positive cells, and from fibroblast feeder cells. Keywords = ES cell Keywords = nestin positive cells Keywords = feeder layer Keywords: other

2005-09-17 | GSE2375 | GEO

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