An essential role for a MEK-C/EBP pathway during growth factor-regulated cortical neurogenesis.
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.
Ménard
Catherine
C
Centre for Neuronal Survival and Brain Tumor Research Centre, Montreal Neurological Institute, Montreal, Canada.
Hein
Paul
P
Paquin
Annie
A
Savelson
Aviva
A
Yang
Xiu Ming
XM
Lederfein
Doron
D
Barnabé-Heider
Fanie
F
Mir
Alain A
AA
Sterneck
Esta
E
Peterson
Alan C
AC
Johnson
Peter F
PF
Vinson
Charles
C
Miller
Freda D
FD
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D005333:Fetus; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D006133:Growth Substances / Q000378:metabolism* / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014404:Tubulin / Q000235:genetics / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; D020934:Ciliary Neurotrophic Factor; C497250:Ddit3 protein, mouse; D006133:Growth Substances; D014157:Transcription Factors; D014404:Tubulin; D051742:Transcription Factor CHOP; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases