Block of c-Fos and JunB expression by antisense oligonucleotides inhibits light-induced phase shifts of the mammalian circadian clock.
Light-induced phase shifts of circadian rhythmic locomotor activity are associated with the expression of c-Jun, JunB, c-Fos and FosB transcription factors in the rat suprachiasmatic nucleus, as shown in the present study. In order to explore the importance of c-Fos and JunB, the predominantly expressed AP-1 proteins for the phase-shifting effects of light, we blocked the expression of c-Fos and JunB in the suprachiasmatic nucleus of male rats, housed under constant darkness, by intracerebroventricular application of 2 microliters of 1 mM antisense phosphorothioate oligodeoxynucleotides (ASO) specifically directed against c-fos and junB mRNA. A light pulse (300 lux for 1 h) at circadian time 15 induced a significant phase shift (by 125 +/- 15 min) of the circadian locomotor activity rhythm, whereas application of ASO 6 h before the light pulse completely prevented this phase shift. Application of control nonsense oligodeoxynucleotides had no effect. ASO strongly reduced the light-induced expression of c-Fos and JunB proteins. In contrast, light pulses with or without the control nonsense oligodeoxynucleotides evoked strong nuclear c-Fos and JunB immunoreactivity in the rat suprachiasmatic nucleus. These results demonstrate for the first time that inducible transcription factors such as c-Fos and JunB are an essential part of fundamental biological processes in the adult mammalian nervous system, e.g. of light-induced phase shifts of the circadian pacemaker.
Wollnik
F
F
Faculty of Biology, University of Konstanz, Germany.
Brysch
W
W
Uhlmann
E
E
Gillardon
F
F
Bravo
R
R
Zimmermann
M
M
Schlingensiepen
K H
KH
Herdegen
T
T
D000818:Animals; D001483:Base Sequence; D002940:Circadian Rhythm / Q000502:physiology* / Q000528:radiation effects*; D007276:Injections, Intraventricular; D008027:Light; D008297:Male; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000502:physiology* / Q000528:radiation effects; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D013493:Suprachiasmatic Nucleus / Q000502:physiology
D016376:Oligonucleotides, Antisense; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun