Abstract
Mammalian neurogenesis is determined by an interplay between intrinsic genetic mechanisms and extrinsic cues such as growth factors. Here we have defined a signaling cascade, a MEK-C/EBP pathway, that is essential for cortical progenitor cells to become postmitotic neurons. Inhibition of MEK or of the C/EBP family of transcription factors inhibits neurogenesis while expression of a C/EBPbeta mutant that is a phosphorylation-mimic at a MEK-Rsk site enhances neurogenesis. C/EBP mediates this positive effect by direct transcriptional activation of neuron-specific genes such as Talpha1 alpha-tubulin. Conversely, inhibition of C/EBP-dependent transcription enhances CNTF-mediated generation of astrocytes from the same progenitor cells. Thus, activation of a MEK-C/EBP pathway enhances neurogenesis and inhibits gliogenesis, thereby providing a mechanism whereby growth factors can selectively bias progenitors to become neurons during development.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CCAAT-Enhancer-Binding Proteins / drug effects
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CCAAT-Enhancer-Binding Proteins / genetics
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CCAAT-Enhancer-Binding Proteins / metabolism*
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Cells, Cultured
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Cerebral Cortex / cytology
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Cerebral Cortex / embryology*
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Cerebral Cortex / metabolism
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Ciliary Neurotrophic Factor / metabolism
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Ciliary Neurotrophic Factor / pharmacology
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Fetus
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Gene Expression Regulation, Developmental / drug effects
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Gene Expression Regulation, Developmental / genetics*
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Growth Substances / metabolism*
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Growth Substances / pharmacology
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MAP Kinase Kinase 1
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Mice
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Mitogen-Activated Protein Kinase Kinases / drug effects
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinase Kinases / metabolism*
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Mitogen-Activated Protein Kinases / drug effects
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism
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Neuroglia / drug effects
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Neuroglia / metabolism
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism*
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Phosphorylation / drug effects
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Promoter Regions, Genetic / drug effects
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Promoter Regions, Genetic / genetics
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Protein Serine-Threonine Kinases / drug effects
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Stem Cells / cytology
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Stem Cells / drug effects
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Stem Cells / metabolism*
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Transcription Factor CHOP
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Transcription Factors / drug effects
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tubulin / genetics
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Tubulin / metabolism
Substances
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CCAAT-Enhancer-Binding Proteins
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Ciliary Neurotrophic Factor
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Ddit3 protein, mouse
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Growth Substances
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Transcription Factors
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Tubulin
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Transcription Factor CHOP
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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Map2k1 protein, mouse
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Mitogen-Activated Protein Kinase Kinases