Cell fate determination in the central nervous system governed by a cytokine-mediated transcriptional network and epigenetic DNA modification.
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概要
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Neurons, astrocytes and oligodendrocytes arise from common progenitor cells that reside in the neuroepithelium of the developing brain. We have focused on cytokines as astrocyte-inducing cell external cues, and found that leukemia inhibitory factor (LIF) and bone morphogenetic protein 2 (BMP2) synergistically induce glial fibrillary acidic protein (GFAP)-positive astrocytes. The synergistic action of these two cytokines is achieved by the complex formation between respective downstream transcription factors, STAT3 and Smad1, bridged by a transcriptional coactivator p300. Simultaneously, BMP2 also represses the differentiation of neurons by inducing anti-neurogenic basic helix-loop-helix (bHLH) transcription factors, Id1, Id3 and Hes-5. Astrocyte-inducing cytokines not only promote astrocytogenesis but also inhibit neurogenesis, suggesting the presence of negative interaction between neuronal and astrocytic differentiation pathways. We also found that oligodendrocytic bHLH factor OLIG2 inhibits the LIF-induced transcription of GFAP gene by abolishing the complex formation between STAT3 and p300. This suggests the presence of negative interaction between astrocytic and oligodendrocytic cell lineages, same as has been observed for neuronal and astrocytic cell lineages. Interestingly, differentiation of neuroepithelial cells depends on cell intrinsic programs, in addition to cell external cues. In contrast to embryonic day 14.5 (E14.5) neuroepithelial cells, LIF is not sufficient to induce GFAP expression in E11.5 neuroepithelial cells. Analysis of the GFAP gene promoter revealed that CpG dinucleotide sequences within the STAT3 recognition site is methylated in E11.5 neuroepithelial cells, and this methylation leads to the inaccessibility of activated STAT3 to its binding elements. The methylation frequency in the STAT3 binding site in the GFAP promoter declines as the developmental process proceeds, allowing the expression of GFAP in astrocytic cell lineage. The results suggest that lineage specification is regulated by cell-external cues and cell-intrinsic programs, where the former involves extracellular cytokines and the latter includes DNA methylation of cell lineage specific gene promoters. Our work also suggests the presence of negative regulatory interactions among the signals that promote differentiation of neurons, astrocytes and oligodendrocytes.
- 日本電気泳動学会の論文
日本電気泳動学会 | 論文
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