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The Circadian Timekeeping System of Drosophila Review

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The Circadian Timekeeping System of Drosophila Review Current Biology, Vol. 15, R714–R722, September 6, 2005, ©2005 Elsevier Ltd. All rights reserved. DOI 10.1016/j.cub.2005.08.019 The Circadian Timekeeping System of Review Drosophila Paul E. Hardin products, in particular, whether they are thought to activate transcription, to repress transcription, to alter protein stability or subcellular localization, or to Daily rhythms in behavior, physiology and degrade proteins. In the transcriptional activator cat- metabolism are controlled by endogenous circadian egory are two basic-helix-loop-helix/PAS domain clocks. At the heart of these clocks is a circadian transcription factors, Clock (Clk) and Cycle (Cyc), oscillator that keeps circadian time, is entrained by which form heterodimers to activate transcription environmental cues such as light and activates [2–4], and one basic-leucine zipper transcription rhythmic outputs at the appropriate time of day. factor, Par domain protein 1ε (PDP1ε) [5]. The Genetic and molecular analyses in Drosophila have transcriptional repressor category includes Period revealed important insights into the molecules and (Per), another PAS domain protein, and Timeless (Tim), mechanisms underlying circadian oscillator function which function as heterodimers to inhibit Clk–Cyc in all organisms. In this review I will describe the function [4], and the basic-leucine zipper transcrip- intracellular feedback loops that form the core of the tional repressor Vrille (Vri) [5–7]. Drosophila circadian oscillator and consider how The category of proteins that alter protein stability they are entrained by environmental light cycles, and subcellular localization includes kinases that where they operate within the fly and how they are destabilize proteins that control clock gene transcrip- thought to control overt rhythms in physiology and tion: the mammalian casein kinase 1ε (CK1ε) homolog behavior. I will also discuss where work remains to Doubletime (Dbt), also known as Discs overgrown or be done to give a comprehensive picture of the Dco, destabilizes Per [8,9]; casein kinase 2 (CK2), circadian clock in Drosophila and likely many other which has α and β subunits, destabilizes Per and also organisms. affects its nuclear localization [10,11]; and the glucose synthase kinase 3 (GSK3) homolog Shaggy (Sgg) phosphorylates Tim to promote nuclear localization of Per–Tim heterodimers [12]. In contrast to the destabi- Introduction lizing effects of the protein kinases, protein phos- Circadian clocks regulate rhythmic phenomena in phatase 2a (PP2a), which has regulatory subunits animals, plants, fungi and even some prokaryotes. In Twins (Tws) and Widerborst (Wdb), stabilizes Per via Drosophila, these clocks control a number of rhythmic dephosphorylation [13]. The protein degradation cat- outputs, including adult emergence (eclosion), egory includes the F-Box/WD40 protein Slimb (Slmb), locomotor activity and olfactory physiology. The which targets phosphorylated Per for degradation in molecular nature of the Drosophila clock is being the proteasome [14,15]. elucidated at a rapid pace, and serves as a good Having introduced the key components of the model for clocks in other animals given that many of Drosophila clock, in the next section I will focus on the components have been conserved. Moreover, their roles within the circadian oscillator. clocks enable an organism to adapt to daily environ- mental cycles by mechanisms that are starting to be Molecular Circuitry of the Drosophila Circadian uncovered in Drosophila. After an initial description of Oscillator Drosophila clock components, I will focus on the The Drosophila circadian oscillator is composed of intracellular feedback loops that lie at the center of the two intracellular feedback loops in gene expression: a circadian oscillator and how they are entrained by Per/Tim loop and a Clk loop [16,17]. Within these light. I will then describe where these oscillators feedback loops, rhythmic transcription of particular operate in adult flies, the rhythmic outputs they are clock genes is controlled via feedback from their own known or suspected to control, and how these protein products. Post-translational mechanisms rhythms are proposed to be controlled, before control the levels and subcellular localization of clock concluding with a perspective on the direction and proteins so that transcriptional feedback occurs at the significance of future work on the Drosophila clock. appropriate time of day. These feedback loops use different mechanisms to regulate transcription in Components of the Drosophila Circadian Clock different phases of the circadian cycle, yet are Genetic analysis has revealed a number of ‘clock’ interlocked by their requirement for Clk–Cyc genes that are critical for clock function in Drosophila dependent transcription. The Per/Tim loop is required (reviewed in [1]). These genes can be divided up for the function of both loops, and will thus be roughly according to the molecular nature of their described first. The Per/Tim Feedback Loop Department of Biology and Biochemistry, University of To initiate the Per/Tim feedback loop, Clk–Cyc Houston, 4800 Calhoun Road, Houston, Texas 77204-5001, heterodimers bind E-box regulatory elements from USA. E-mail: [email protected] mid-day through early night, thereby activating Current Biology R715 Figure 1. Model of the Per/Tim feed- P Tim back loop. Sgg Clk–Cyc heterodimers bind to E-boxes P Per and activate transcription of Per and Dbt Tim Tim. As Per is produced it is phospho- P Per Dbt rylated by Dbt and CK2, which leads Clk Cyc Per, Tim to its degradation. Tim binds to, and E-Box stabilizes, phosphorylated Per, which X P Tim P PP2a remains bound to Dbt. Per is also sta- X P P P Per P bilized by PP2a, which removes phos- Tim X phates that were added to Per. The P Per P Clk Tim–Per–Dbt complexes are phospho- Dbt P P Per Clk Cyc rylated by Sgg which, in concert with P P Tim phosphorylation by CK2, promotes P Per, Tim their transport into the nucleus. E-Box Tim–Per–Dbt complexes then bind to Per X P Per Clk–Cyc, thereby removing Clk–Cyc from the E-box and inhibiting Per and Clk Cyc CK2 Tim transcription. Per and Clk are then Dbt Per, Tim destabilized, via Dbt phosphorylation, E-Box and degraded, whereas Tim degrada- Clk Cyc tion (at least in response to light) is Nucleus Cytoplasm triggered by tyrosine phosphorylation. Current Biology The accumulation of non-phosphory- lated (or hypophosphorylated) Clk leads to heterodimerization with Cyc and another cycle of Per and Tim transcription. Solid lines with arrow, sequential steps in the feed- back loop; blocked line, inhibitory interaction; wavy line, Per and Tim mRNA; double arrow line, reversible phosphorylation; dashed lines, proteasomal degradation; black X, degraded proteins; P, protein phosphorylation; double line, nuclear membrane. transcription of the Per and Tim genes (Figure 1) Clk mRNA (see below) and activates E-box dependent [4,18–20]. The levels of Per and Tim transcripts peak transcription, thus starting the next transcriptional early in the night, whereas Per and Tim proteins do cycle (Figure 1). In addition to activating Per and Tim, not accumulate to peak levels until late evening Clk–Cyc directly activates Vri and Pdp1ε within the Clk [16,21–26]. This delay is the result of phosphorylation loop and a subset of clock output genes (see below). dependent destabilization of Per by Dbt, and possibly also CK2, followed by stabilization of phosphorylated The Clk Feedback Loop Per by Tim binding [8,9,11,27]. Per is also stabilized by In the Clk feedback loop, Clk–Cyc binds E-boxes to PP2a, which is thought to remove the phosphates activate high levels of Vri and Pdp1ε expression added by Dbt and CK2 [13]. during the late day and early night (Figure 1) [5–7]. Vri Dbt remains bound to Per to form a Per–Tim–Dbt accumulates in phase with its mRNA and binds complex, and the entire complex (or possibly just Tim) Vri/PDP1ε box (V/P box) regulatory elements to inhibit is translocated into the nucleus upon Sgg-dependent Clk transcription [5,7]. Consequently, Clk mRNA Tim phosphorylation and CK2-dependent Per cycles in the opposite phase as Clk–Cyc/E-box regu- phosphorylation [10–12,28–30]. Once in the nucleus, lated transcripts [5,7]. PDP1ε accumulates to high Per continues to be phosphorylated by Dbt, and this levels during the mid to late evening and activates Clk phosphorylation potentiates Per’s ability to repress transcription [5]. In vitro experiments showed that transcription [27]. Per appears to be a more potent PDP1ε can compete with Vri for binding to V/P-boxes, inhibitor of Clk–Cyc dependent transcription than suggesting a model in which increasing levels of Per–Tim [29,31], consistent with the observation that PDP1ε displace Vri from V/P-boxes and activate Clk Tim falls to low levels several hours before Per [26]. transcription [5]. Though attractive, this model does From the results of in vitro experiments, Per is not explain the constant peak levels of Clk expression thought to repress Clk–Cyc dependent transcription in non-functional ClkJrk and cyc01 mutants [17], which by binding to Clk and inhibiting the DNA binding virtually eliminate Vri and Pdp1ε expression [5]. To activity of Clk–Cyc dimers [32]. Recent in vivo analysis accommodate the ClkJrk and cyc01 results, a clock has not only confirmed this mode of regulation, but independent activator may drive constitutive Clk also suggests that Dbt dependent phosphorylation transcription, which is then rhythmically modulated by destabilizes Clk, explaining the coincidence between Vri and PDP1ε (Figure 2). phospho-Per and phospho-Clk levels (W. Yu, personal A common feature of the Per/Tim and Clk feedback communication). In addition, a more stringent extrac- loops is the activation of rhythmic transcription by tion procedure revealed that hypophosphorylated Clk Clk–Cyc. As rhythmic transcription of Clk–Cyc accumulates in antiphase to hyperphosphorylated Clk; activated genes requires feedback by Per–Tim, this thus, hypophosphorylated Clk accumulates in phase implies that the Per/Tim loop is also required for the with Per, Tim and other E-box/Clk-Cyc dependent Clk loop.
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