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Circadian Systems: Different Levels of Complexity doi 10.1098/rstb.2001.0969 Circadian systems: different levels of complexity Till Roenneberg* and Martha Merrow Institute for Medical Psychology, Chronobiology, Goethestrasse 31, D-80336 MÏnchen, Germany After approximately 50 years of circadian research, especially in selected circadian model systems (Drosophila, Neurospora, Gonyaulax and, more recently, cyanobacteria and mammals), we appreciate the enormous complexity of the circadian programme in organisms and cells, as well as in physiological and molecular circuits. Many of our insights into this complexity stem from experimental reductionism that goes as far as testing the interaction of molecular clock components in heterologous systems or in vitro. The results of this enormous endeavour show circadian systems that involve several oscillators, multiple input pathways and feedback loops that contribute to speci¢c circadian qualities but not necessarily to the generation of circadian rhythmicity. For a full appreciation of the circadian programme, the results from di¡erent levels of the system eventually have to be put into the context of the organism as a whole and its speci¢c temporal environment. This review summarizes some of the complexities found at the level of organisms, cells and molecules, and highlights similar strategies that apparently solve similar problems at the di¡erent levels of the circadian system. Keywords: circadian; model; Neurospora; feedback; transcription; Zeitnehmer undamped, although the clock would get its daily kick in 1. INTRODUCTION nature? What is the function of temperature compensa- At one end, circadian complexity involves the organism's tion? Perhaps the solutions to these questions are rooted entire physical and biological environmentöwith all in the system's complexity both at the anatomical and participants (rotation of earth, food, predators, etc.) molecular level. somehow being oscillators. At the other extreme, a set of The question of where the clock resides in animals has genes forms a feedback loop. A strategy to cope with been approached by ablation and transplantation experi- complexity is to reduce the number of variables in experi- ments (e.g. Richter 1967; Ralph et al. 1990). Ablation of ments and to control those remaining. As a ¢rst step in identi¢ed pacemakers, e.g. the suprachiasmatic nuclei circadian research, organisms were isolated from their (SCN) results in loss of rhythmicity and their transplan- environmentösubjected to only one zeitgeber or to tation rescues rhythmicity together with other circadian constant conditions. Fundamental ¢ndings resulted from qualities. Yet even without these pacemakers, organisms this approach: rhythmicity continues unabated in can still consolidate circadian behaviour under special constant conditions, it can be entrained, in de¢ned conditions. Other oscillators must therefore remain, but ranges, to 24-hour and non-24-hour cycles (e.g. by using what are they and why are there so many? light as the zeitgeber), and it appears to defy biochemical After isolating the organism from its `noisy' environ- logic by compensating its period for di¡erent constant ment, central pacemakers can be isolated from the `noisy' temperatures. These characteristics can be broken down rest of the organism and still maintain their circadian into the following six qualities which are common to all properties in vitro. Even when individual pacemaker cells circadian systems (Roenneberg & Merrow 1998): are separated, they continue to generate circadian rhythmicity. However, the properties of the single cell (i) Rhythmicity as such (independent of its frequency). rhythmicity are di¡erent from those of the network. As (ii) The circadian range of the period. independent cells, they oscillate with di¡erent periods and (iii) An amplitude su¤ciently robust to drive output out of phase (Welsh et al. 1995). Networks are therefore rhythms. important for uniform and robust rhythmicity of the (iv) The fact that the rhythmicity is su¤ciently self- organism but not for the generation of the oscillation, sustained to continue unabated. which is cellular. Furthermore, self-sustained cellular oscil- (v) Temperature compensation. lation is not con¢ned to pacemaker cellsöessentially the (vi) Entrainability. same molecular clocks appear to tick in cells of di¡erent Despite our de¢nition of circadian systems and their tissues, from brain to liver in mammals and ¢sh (Whitmore qualities, many important questions remain unanswered. et al. 2000; Yamazaki et al. 2000), from head to wings in Why, for example, is circadian rhythmicity potentially Drosophila (Plautz et al. 1997). Like in the ecosystem, chains of oscillators form networks and potentially feed back on or *Author for correspondence ([email protected]). modulate each other within an organism. Phil. Trans. R. Soc. Lond. B(2001)356,1687^1696 1687 & 2001 The Royal Society 1688 T. Roenneberg and M. Merrow Circadian complexity Experimental veri¢cation of `clock gene' function has unidenti¢ed, circadian centres that are postulated, based been approached in analogous ways to experiments at the on experiments in SCN-lesioned rats (e.g. amphetamine- anatomical level, i.e. deletion and re-introduction of a dependent activity rhythms, Honma et al. 1987). In addi- `clock gene' go together with loss and rescue of rhythmi- tion, pacemaker centres must exist in parallel to the SCN- city, with circadian qualities linked to a gene (Dunlap based circadian system. An anticipatory locomotor beha- 1999). The complexity problem also extends analogously viour in rodents can be entrained by food without from the anatomical to the cellular^molecular levelö entraining the SCN-controlled activity rhythm (Ascho¡ without a `clock gene', an entrainable oscillator remains 1987).The characteristics of this food entrainable oscillator (Merrow et al. 1999) and single cells may even accommo- (FEO) are similar to but separate from the circadian date more than one circadian oscillator (Roenneberg & system. Morse 1993). So, the circadian complexity known from Mainly based on monitoring mRNAs of known `clock the higher levels can even be demonstrated within the genes' (Balsalobre et al. 1998) or by using light-emitting cell. reporter constructs combining clock-controlled promoters In spite of all this reductionism, complexity reappears, and a luciferase gene, many autonomous circadian clocks although the players changeöorganisms, cells, molecules. have been discovered outside of the brain in insects and By comparing strategies at the di¡erent levels, we learn vertebrates (Hege et al.1997;Plautzet al. 1997; Whitmore how (and possibly why) elements are put together. By et al. 2000; Yamazaki et al. 2000; Giebultowicz 2001). In characterizing more of the players and discovering how spite of the identi¢cation of molecular circadian clocks in they interact, we will ¢nally understand how the system many mammalian peripheral tissues and cells, the role worksasanentity. of the SCN as a central pacemaker is unchallenged (Yamazaki et al. 2000). The di¡erent body clocks have di¡erent qualities with fundamental di¡erences between 2. CIRCADIAN COMPLEXITY WITHIN THE ORGANISM the molecular clock of SCN neurones and those of The mammalian pacemaker resides in the SCN peripheral cells. While a cultured SCN oscillates without (¢gure 1) and drives the rhythmic melatonin production damping as long as the cells can be kept alive in culture, in the pinealöbut, unlike in many other vertebrates, the peripheral oscillators damp within one or two cycles production of melatonin is not rhythmic in the isolated (Yamazaki et al. 2000). Damping is prevented when the pineal. The fact that pineal melatonin production is culture medium is regularly refreshed, suggesting that driven by the SCN in mammals does not mean that the peripheral molecular oscillators have to be regularly mammalian pinealocytes do not contain a cellular^ re-initiated (or re-entrained among each other). There molecular circadian clock, as do many other cells and are at least two possible explanations for the di¡erences tissues (Yamazaki et al. 2000). Recent experiments indi- between cellular clocks in the pacemaker and in the cate that `clock gene' RNAs also cycle in isolated pineals periphery. Either the molecular machinery responsible (S. Yamazaki, M. Abe, E. D. Herzog and M. Menaker, for their circadian rhythmicity is put together di¡erently personal communication; G. Tosini, personal communica- or SCN neurones produce output signals (which can feed tion). Thus, pinealocytes apparently contain a molecular back and sustain the oscillation) while peripheral cells clocköonly their melatonin production depends on SCN only organize their own metabolism on a circadian scale control via a multisynaptic pathway. The SCN as a circa- without exporting circadian signals. The issue of feed- dian structure did not ¢rst appear with the evolution of back and self-sustainment will be discussed in more mammals as non-mammalian vertebrates also possess a detail below (see ½ 4). hypothalamic circadian clock, so that at least two auto- Clocks are thought to have evolved because entrain- nomous pacemakers coordinate their endogenous daily ment of an oscillator apparently allows more £exibility programme (we know the most the about their interplay than merely being driven by the cyclic environment from experiments with sparrows, e.g. Takahashi & (Pittendrigh 1960; Yan et al. 1998). The same argument Menaker 1979; Takahashi et al. 1980; Heigl & Gwinner holds for
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