Molecular mechanisms regulating NGF-mediated enhancement of cholinergic neuronal phenotype: c-fos trans-activation of the choline acetyltransferase gene.
Nerve growth factor (NGF) enhances expression of the cholinergic phenotype observed as increased choline acetyltransferase (ChAT) activity, immunoreactivity, and mRNA. In the present study, treatment of cultured rat embryonic basal forebrain neurons with anti-c-fos, prior to administering NGF, blocked NGF-mediated increases in ChAT activity by 67%; basal ChAT activity was not affected by the antisense oligonucleotide treatment. Reverse transcription-polymerase chain reaction (RT-PCR) revealed that anti-c-fos treatment resulted in not only blockade but enhancement of steady-state ChAT mRNA at different time points. These data suggest that c-fos is an important component in NGF-mediated changes in the cholinergic phenotype and support the hypothesis that c-fos plays a role in the regulation of transcription of the ChAT gene. Elucidation of mechanisms underlying this regulation may aid drug development in neurodegenerative disease.
Pongrac
J L
JL
Department of Pharmacology, University of Western Ontario, London, Canada.
Rylett
R J
RJ
D000109:Acetylcholine / Q000378:metabolism*; D017398:Alternative Splicing; D000818:Animals; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D016762:Genes, fos / Q000235:genetics; D007150:Immunohistochemistry; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D016548:Prosencephalon / Q000187:drug effects / Q000196:embryology / Q000201:enzymology / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection
D009414:Nerve Growth Factors; D016376:Oligonucleotides, Antisense; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine