Blocked MAP kinase activity selectively enhances neurotrophic growth responses.
Bone morphogenetic proteins (BMPs) 4 and 6 as well as MEK inhibitors PD98059 and U0126 potentiate neurotrophin 3 (NT3)- and neurturin (NTN)-induced neurite outgrowth and survival of peripheral neurons from the E9 chicken embryo. Preexposure to BMP4 or PD98059 was sufficient to prime the potentiation of subsequently added NT3. Phosphorylation of Erk2, induced by NT3, was reduced by MEK inhibition but unaffected by BMP signaling. Real-time PCR showed that neither BMP stimulation nor MEK inhibition increased Trk receptor expression and that the BMP-induced genes Smad6 and Id1 were not upregulated by PD98059. In contrast, both MEK inhibition and BMP signaling suppressed transcription of the serum-response element (SRE)-driven Egr1 gene. A reporter assay using NGF-stimulated PC12 cells demonstrated that MEK/Erk/Elk-driven transcriptional activity was inhibited by Smad1/5 and by PD98059. Thus, suppression of SRE-controlled transcription represents a likely convergence point for pathways regulating neurotrophic responses.
Althini
Susanna
S
Department of Neuroscience, Unit for Developmental Neuroscience, Biomedical Centre, Uppsala University, Uppsala, Sweden.
Usoskin
Dmitry
D
Kylberg
Annika
A
Kaplan
Paul L
PL
Ebendal
Ted
T
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005724:Ganglia / Q000166:cytology / Q000201:enzymology* / Q000254:growth & development; D005809:Genes, Regulator / Q000187:drug effects / Q000235:genetics; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D020933:Neurotrophin 3 / Q000378:metabolism / Q000494:pharmacology; D016716:PC12 Cells; D017933:Peripheral Nervous System / Q000166:cytology / Q000201:enzymology* / Q000254:growth & development; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics; D051381:Rats; D027602:Serum Response Element / Q000187:drug effects / Q000235:genetics; D051785:Smad Proteins; D051898:Smad1 Protein; D015534:Trans-Activators / Q000378:metabolism / Q000494:pharmacology; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; C494114:Elk1 protein, rat; D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D011518:Proto-Oncogene Proteins; D051785:Smad Proteins; D051898:Smad1 Protein; C497400:Smad1 protein, rat; D015534:Trans-Activators; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D019950:Mitogen-Activated Protein Kinase 1; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases