title: CRTC Potentiates Light-independent timeless Transcription to Sustain Circadian Rhythms in Drosophila.
abstract: Light is one of the strongest environmental time cues for entraining endogenous circadian rhythms. Emerging evidence indicates that CREB-regulated transcription co-activator 1 (CRTC1) is a key player in this pathway, stimulating light-induced Period1 (Per1) transcription in mammalian clocks. Here, we demonstrate a light-independent role of Drosophila CRTC in sustaining circadian behaviors. Genomic deletion of the crtc locus causes long but poor locomotor rhythms in constant darkness. Overexpression or RNA interference-mediated depletion of CRTC in circadian pacemaker neurons similarly impairs the free-running behavioral rhythms, implying that Drosophila clocks are sensitive to the dosage of CRTC. The crtc null mutation delays the overall phase of circadian gene expression yet it remarkably dampens light-independent oscillations of TIMELESS (TIM) proteins in the clock neurons. In fact, CRTC overexpression enhances CLOCK/CYCLE (CLK/CYC)-activated transcription from tim but not per promoter in clock-less S2 cells whereas CRTC depletion suppresses it. Consistently, TIM overexpression partially but significantly rescues the behavioral rhythms in crtc mutants. Taken together, our data suggest that CRTC is a novel co-activator for the CLK/CYC-activated tim transcription to coordinate molecular rhythms with circadian behaviors over a 24-hour time-scale. We thus propose that CRTC-dependent clock mechanisms have co-evolved with selective clock genes among different species.
authors: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
authors: Minkyung
authors: M
authors: Kim
authors: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
authors: Hoyeon
authors: H
authors: Lee
authors: UNIST-Olympus Biomed Imaging Center (UOBC), UNIST, Ulsan 44919, Republic of Korea.
authors: Jin-Hoe
authors: JH
authors: Hur
authors: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
authors: Joonho
authors: J
authors: Choe
authors: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
authors: Chunghun
authors: C
authors: Lim
mesh_terms: D000818:Animals; D002940:Circadian Rhythm / Q000502:physiology*; D029721:Drosophila Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D005786:Gene Expression Regulation / Q000502:physiology*; D008027:Light; D009154:Mutation; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: C578084:CRTC protein, Drosophila; D029721:Drosophila Proteins; D056950:Period Circadian Proteins; D014157:Transcription Factors; C096445:tim protein, Drosophila