P149
CREB co-activator CRTC regulates the circadian clock in Drosophila
melanogaster
Minkyung Kim , Chunghun Lim , Joonho Choe
1
2
1
1Biological Sciences, KAIST, Daejeon, KOREA SOUTH
2UNIST, Ulsan, Ulsan, KOREA, REPUBLIC OF
CREB-dependent transcription has long been implicated as an integrating step of light entrainment in
circadian clocks. Emerging evidence suggest that CREB-regulated transcription co-activator 1 (CRTC1) is a
key player in this pathway. Light-induced activation of CRTC1 stimulates the transcription of mammalian
Period1 gene. Moreover, CRTC1 and its regulator salt-inducible kinase 1 (SIK1) constitute a negative
feedback to buffer light-induced phase resetting of mammalian clocks. Here we show Drosophila CRTC
plays more pivotal roles in circadian rhythms. CRTC null mutant flies exhibited poor locomotor rhythms in
constant darkness (DD) conditions. Overexpression or RNA interference (RNAi)-mediated depletion of
CRTC in pacemaker neurons similarly led to the arrhythmic circadian behaviors, indicating that Drosophila
circadian clocks are sensitive to the dosage of CRTC proteins. In DD cycles, oscillating expression of two
circadian clock proteins PERIOD (PER) and TIMELESS (TIM) were phase-delayed by CRTC mutation. At
transcript levels, the phase delay was more evident in rhythmic expression of tim mRNA, suggesting that tim
promoter might be one of major transcriptional targets of CRTC. Indeed, CRTC overexpression enhanced
baseline as well as CLOCK/CYCLE-activated transcription from a reporter gene containing tim promoter in
transfected S2 cells. Taken together, our data demonstrate a light-independent role of CRTC in timing clock
gene expression, thus revealing a novel transcriptional mechanism in core clocks to sustain free-running
circadian behaviors.