Unknown,Transcriptomics,Genomics,Proteomics

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Effects of fibroblast growth factors (FGF) on dissociated myelinating cultures

ABSTRACT: Analysis of the effects of three members of the FGF family (FGF1, FGF2 and FGF9) and bone morphogenic protein 4 (BMP4) on myelinating cultures generated from dissociated embryonic spinal cord. The results of both immediate (24 hours, T1 (24 hrs)) and long term treatments (10days, T2) give insights into the cumulative effects of sustained FGF and BMP mediated signal transduction in the pathogenesis of demyelinating diseases. Dissociated myelinating cultures were generated from neurosphere derived astrocytes (generated from striata of P1 Sprague-Dawley rats) and spinal cord cells from E15.5 Sprague-Dawley(SD) embryos. The effect of recombinant human FGF9 and other soluble factors on these in vitro myelinating cultures was investigated by adding them to the culture media after 18 days in vitro (DIV). The effects of each factor were analysed using three independent cultures at two time points (19DIV and 28 DIV).

ORGANISM(S): Rattus norvegicus

SUBMITTER: Chris Linington

PROVIDER: E-GEOD-52753 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:BACKGROUND: The polycomb group protein Ezh2 is an epigenetic repressor of transcription originally found to prevent untimely differentiation of pluripotent embryonic stem cells. We previously demonstrated that Ezh2 is also expressed in multipotent neural stem cells (NSCs). We showed that Ezh2 expression is downregulated during NSC differentiation into astrocytes or neurons. However, high levels of Ezh2 remained present in differentiating oligodendrocytes until myelinating. This study aimed to elucidate the target genes of Ezh2 in NSCs and in premyelinating oligodendrocytes (pOLs). METHODOLOGY/PRINCIPAL FINDINGS: We performed chromatin immunoprecipitation followed by high-throughput sequencing to detect the target genes of Ezh2 in NSCs and pOLs. We found 1532 target genes of Ezh2 in NSCs. During NSC differentiation, the occupancy of these genes by Ezh2 was alleviated. However, when the NSCs differentiated into oligodendrocytes, 393 of these genes remained targets of Ezh2. Analysis of the target genes indicated that the repressive activity of Ezh2 in NSCs concerns genes involved in stem cell maintenance, in cell cycle control and in preventing neural differentiation. Among the genes in pOLs that were still repressed by Ezh2 were most prominently those associated with neuronal and astrocytic committed cell lineages. Suppression of Ezh2 activity in NSCs caused loss of stem cell characteristics, blocked their proliferation and ultimately induced apoptosis. Suppression of Ezh2 activity in pOLs resulted in derangement of the oligodendrocytic phenotype, due to re-expression of neuronal and astrocytic genes, and ultimately in apoptosis. CONCLUSIONS/SIGNIFICANCE: Our data indicate that the epigenetic repressor Ezh2 in NSCs is crucial for proliferative activity and maintenance of neural stemness. During differentiation towards oligodendrocytes, Ezh2 repression continues particularly to suppress other neural fate choices. Ezh2 is completely downregulated during differentiation towards neurons and astrocytes allowing transcription of these differentiation programs. The specific fate choice towards astrocytes or neurons is apparently controlled by epigenetic regulators other than Ezh2. Examination of Ezh2 target sites in 2 different primary cells types

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Effects of fibroblast growth factors (FGF) on dissociated myelinating cultures

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