Abstract
Human embryonic stem cells (hESCs) offer a platform to bridge what we have learned from animal studies to human biology. Using oligodendrocyte differentiation as a model system, we show that sonic hedgehog (SHH)-dependent sequential activation of the transcription factors OLIG2, NKX2.2 and SOX10 is required for sequential specification of ventral spinal OLIG2-expressing progenitors, pre-oligodendrocyte precursor cells (pre-OPCs) and OPCs from hESC-derived neuroepithelia, indicating that a conserved transcriptional network underlies OPC specification in human as in other vertebrates. However, the transition from pre-OPCs to OPCs is protracted. FGF2, which promotes mouse OPC generation, inhibits the transition of pre-OPCs to OPCs by repressing SHH-dependent co-expression of OLIG2 and NKX2.2. Thus, despite the conservation of a similar transcriptional network across vertebrates, human stem/progenitor cells may respond differently to those of other vertebrates to certain extrinsic factors.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Differentiation*
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Cells, Cultured
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Embryonic Stem Cells / cytology*
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Fibroblast Growth Factor 2 / pharmacology*
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Gene Expression Regulation
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Hedgehog Proteins / genetics
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Hedgehog Proteins / metabolism*
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Homeobox Protein Nkx-2.2
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Microscopy, Electron
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Myelin Sheath / metabolism
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Myelin Sheath / ultrastructure
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism
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Nuclear Proteins
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Oligodendrocyte Transcription Factor 2
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Oligodendroglia / cytology
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Oligodendroglia / drug effects*
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Oligodendroglia / metabolism*
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Signal Transduction / drug effects*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Zebrafish Proteins
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Hedgehog Proteins
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Homeobox Protein Nkx-2.2
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Homeodomain Proteins
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NKX2-2 protein, human
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Nerve Tissue Proteins
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Nkx2-2 protein, mouse
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Nuclear Proteins
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OLIG2 protein, human
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Oligodendrocyte Transcription Factor 2
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SHH protein, human
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Transcription Factors
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Zebrafish Proteins
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nkx2.2b protein, zebrafish
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Fibroblast Growth Factor 2