An essential role for a MEK-C/EBP pathway during growth factor-regulated cortical neurogenesis

Neuron. 2002 Nov 14;36(4):597-610. doi: 10.1016/s0896-6273(02)01026-7.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Proteins / drug effects
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / embryology*
  • Cerebral Cortex / metabolism
  • Ciliary Neurotrophic Factor / metabolism
  • Ciliary Neurotrophic Factor / pharmacology
  • Fetus
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / genetics*
  • Growth Substances / metabolism*
  • Growth Substances / pharmacology
  • MAP Kinase Kinase 1
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / drug effects
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Neuroglia / drug effects
  • Neuroglia / metabolism
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Phosphorylation / drug effects
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / genetics
  • Protein-Serine-Threonine Kinases / drug effects
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stem Cells / metabolism*
  • Transcription Factor CHOP
  • Transcription Factors / drug effects
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tubulin / genetics
  • Tubulin / metabolism

Substances

  • CCAAT-Enhancer-Binding Proteins
  • Ciliary Neurotrophic Factor
  • Ddit3 protein, mouse
  • Growth Substances
  • Transcription Factors
  • Tubulin
  • Transcription Factor CHOP
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • Map2k1 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases