Neurturin suppresses injury-induced neuronal activating transcription factor 3 expression in cultured guinea pig cardiac ganglia.
Cultured guinea pig atrial whole mounts containing the intrinsic cardiac ganglia were used as an in vitro model to investigate the induction of the stress/injury marker activating transcription factor 3 (ATF-3). ATF-3 expression was quantified by using immunocytochemical labeling and real-time PCR. In freshly isolated ganglia, no neuronal or Schwann cell nuclei exhibited ATF-3 immunoreactivity. In 2-hour cultures, the induction of ATF-3 expression was evident in many Schwann cell nuclei, whereas no neuronal nuclei were ATF-3 immunoreactive. Beginning at 4 hours, the percentage of neurons with ATF-3-immunoreactive nuclei increased progressively, and, by 48 hours in culture, approximately 95% of the cardiac neurons had ATF-3-immunoreactive nuclei. Neurturin significantly suppressed ATF-3 expression in 48-hour-cultured neurons without effect on ATF-3 expression in Schwann cell nuclei. Neuturin also could reverse neuronal ATF-3 expression after its induction. The suppression of ATF-3 induction by neurturin was mediated by activation of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. Glial-derived neurotrophic factor (GDNF) also suppressed neuronal ATF-3 induction during culture. However, culture in serum-free media, presence of nerve growth factor, or addition of pituitary adenylate cyclase-activating polypeptide had no effect on ATF-3 induction in the 48-hour-cultured cardiac neurons. By 4 hours in culture, there was a significant increase in ATF-3 transcript levels, and neurturin partially suppressed ATF-3 transcript levels in 48-hour cultures. It is proposed that the loss of target-derived neurturin is a potential mechanism stimulating injury-induced expression of ATF-3 in cardiac neurons.
Young
Beth A
BA
Department of Anatomy and Neurobiology, University of Vermont College of Medicine, Burlington, Vermont 05405, USA.
Girard
Beatrice M
BM
Parsons
Rodney L
RL
D051700:Activating Transcription Factor 3 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005728:Ganglia, Sympathetic / Q000187:drug effects / Q000293:injuries* / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006168:Guinea Pigs; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051101:Neurturin / Q000494:pharmacology* / Q000502:physiology
D051700:Activating Transcription Factor 3; D051101:Neurturin