Abstract
Neurotrophin 3 (NT3) induces mouse cortical stem cells to an asymmetric division from a symmetric division, suggesting that NT3 may work as an early differentiative signal for neural stem cells (NSCs). Here, using cultured post-natal hippocampal stem cells as a model, we demonstrated that NT3-stimulation causes NSCs to differentiate into oligodendrocyte precursors (OLPs) through an extracellular signal-related kinase1/2 (Erk1/2)-dependent pathway. Following the treatment of NT3 for 24 h, NSCs differentiated into more OLPs and fewer neurons, whereas the proliferation and survival of OLPs were not affected. NT3 induced a series of intracellular responses including enhancement of phosphorylation of Erk1/2 or Akt and increase of expression of oligodendrocyte lineage gene (Olig)-1, a transcriptional factor known to participate in oligodendrocyte development. Application of U0126, a specific inhibitor of MEK1/2 which are upstream to Erk1/2, blocked the phosphorylation of Erk1/2, suppressed the expression of Olig-1 and prevented NSC differentiation into OLPs in response to NT3 stimulation. Blockade of TrkC also inhibited the differentiation of NSCs to OLPs induced by NT3. However, administration of LY294002, an inhibitor of phosphatidylinositol 3 kinase (PI3K), blocked the phosphorylation of Akt but did not affect the effect of NT3 on the expression of Olig-1 and on NSC differentiation into OLPs. Taken together, these results suggest that NT3 induce NSCs to differentiate into OLPs by enhancing the expression of Olig-1 through an Erk1/2-dependent pathway.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Basic Helix-Loop-Helix Transcription Factors
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Blotting, Western / methods
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Bromodeoxyuridine
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Butadienes / pharmacology
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Cell Count / methods
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Cell Differentiation / drug effects*
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Cells, Cultured
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Chromones / pharmacology
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DNA-Binding Proteins / metabolism
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Glial Fibrillary Acidic Protein / genetics
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Glial Fibrillary Acidic Protein / metabolism
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Hippocampus / cytology
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Immunohistochemistry / methods
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In Situ Nick-End Labeling / methods
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Indoles
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism*
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Models, Neurological
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Morpholines / pharmacology
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Nerve Tissue Proteins / metabolism
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Neurons / physiology
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Neurotrophin 3 / pharmacology*
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Nitriles / pharmacology
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Oligodendroglia / cytology
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Oligodendroglia / drug effects*
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Phosphatidylinositol 3-Kinases / metabolism
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RNA, Messenger / biosynthesis
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Rats
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Rats, Sprague-Dawley
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Receptor, Platelet-Derived Growth Factor alpha / genetics
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Receptor, Platelet-Derived Growth Factor alpha / metabolism
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Stem Cells / cytology*
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Transcription Factors / metabolism
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Tubulin / genetics
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Tubulin / metabolism
Substances
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Ascl1 protein, rat
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Basic Helix-Loop-Helix Transcription Factors
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Butadienes
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Chromones
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DNA-Binding Proteins
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Enzyme Inhibitors
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Glial Fibrillary Acidic Protein
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Indoles
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Morpholines
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Nerve Tissue Proteins
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Neurotrophin 3
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Nitriles
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Olig1 protein, rat
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RNA, Messenger
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Transcription Factors
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Tubulin
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U 0126
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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DAPI
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Phosphatidylinositol 3-Kinases
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Receptor, Platelet-Derived Growth Factor alpha
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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Bromodeoxyuridine