Regulation of VIP and other neuropeptides by c-Jun in sensory neurons: implications for the neuropeptide response to axotomy.
Peripheral axotomy of adult rat sensory neurons causes induction of the transcription factor c-Jun and increased expression of the neuropeptides vasoactive intestinal polypeptide (VIP), galanin and neuropeptide Y. To determine whether VIP induction is dependent on transcriptional regulation by c-Jun, we exploited the fact that c-Jun and VIP are also induced in cultured sensory neurons. We blocked c-Jun synthesis by microinjecting antisense oligonucleotides and found that VIP expression, determined by quantitative immunofluorescence, was specifically reduced. Blockade of c-June expression also resulted in reduced neuropeptide Y expression but left galanin, substance P and calcitonin gene-related peptide unaffected. Since in vitro electrophoretic mobility shift assays showed that a nominal cyclic AMP responsive element (CRE) associated with the rat VIP gene could bind c-Jun-containing transcription factor complexes, we next investigated whether VIP expression in sensory neurons might depend on transcription factor binding to the CRE. When a DNA plasmid containing multiple copies of the CRE was injected into newly cultured sensory neurons to sequester transcription factors binding the endogenous CRE, there was a selective reduction in VIP expression. VIP induction in sensory neurons therefore probably results from transcriptional activation by c-Jun acting in combination with other factor(s), possibly acting through the CRE. These results show that c-Jun can regulate transcription of other genes affected by axotomy and imply that it could be a key regulator of the neuronal axotomy response.
Mulderry
P K
PK
MRC Brain Metabolism Unit, Royal Edinburgh Hospital, UK.
Dobson
S P
SP
D000818:Animals; D001369:Axons / Q000502:physiology; D002470:Cell Survival; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004247:DNA / Q000494:pharmacology; D003714:Denervation; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D007267:Injections; D009474:Neurons / Q000378:metabolism; D009475:Neurons, Afferent / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D009479:Neuropeptides; D016376:Oligonucleotides, Antisense; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D014660:Vasoactive Intestinal Peptide; D004247:DNA