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* Bio-MAX Institute, and College of Medicine, Seoul National University, Seoul, Korea
Correspondence: Address reprint requests and inquiries to Kwang-Hyun Cho, Tel.: 82-2-887-2650; E-mail: ckh-sb{at}snu.ac.kr.
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ABSTRACT |
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It has been well known that the response of a plant circadian clock to the change of a light period is fast (1
–4) but that of a mammalian circadian clock is relatively slow (5,6). What does cause such a different feature of entrainment? To answer this question, we have investigated the circadian regulatory networks of various species and found that the core circadian regulatory network (CCRN)—the common structure of circadian regulatory networks—of animals is topologically different from that of plants.
The CCRN of plants is composed of two coupled negative feedback loops (NFLs). For instance, in Arabidopsis thaliana, the complex CCA1/LHY suppresses the transcription of TOC1 whose product (protein) activates LHY and CCA1 (7,8). These regulatory relations between TOC1 and LHY/CCA1 constitute an NFL. In addition, the complex CCA1/LHY induces the synthesis of PRR5, 7, 9 which repress the synthesis of CCA1 and LHY. As PRR5, 7, 9 show similar response/regulation patterns (7–9), we can consider these as one component. These regulations form another NFL. Many other plants have clock genes homologous to those of Arabidopsis and their expressions are regulated in a similar way (10–12). Hence, we can regard the CCRN of many plants as that of Arabidopsis (see Fig. 1).
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). This forms an NFL. Note that CLK is the limiting factor in constituting the CLK/CYC complex since CYC is usually highly abundant (13). In addition, the regulatory relations between PDP1 and CLK/CYC constitute a PFL since PDP1 activates the transcription of CLK; the regulatory relations between VRI and CLK/CYC form another NFL since VRI inhibits the transcription of CLK (13,14). As an example of mammals, let us consider the CCRN of a mouse (Mus musculus) that is composed of two NFLs coupled with one PFL as illustrated in Fig. 1. One NFL represents the regulatory relation between CLOCK/BMAL1 and PER/CRY, and the other NFL denotes the regulatory relation between CLOCK/BMAL1 and REV-ERB
. Moreover, the PFL indicates the regulatory relation between ROR and CLOCK/BMAL1 (15). By further investigating circadian regulatory networks of various other species such as Homo sapiens, Bos taurus, and Rattus norvegicus (16), it turns out that the CCRN of animals can be characterized by two NFLs coupled with one PFL as shown in Fig. 1.
A circadian rhythm produces an autonomous oscillation and periodic or aperiodic changes of an external stimulus affect the circadian oscillation. In particular, the shape of the external light-dark (LD) cycle and the interaction mechanism of the light with the circadian regulatory network affect the entrainment characteristics of circadian rhythms. In other words, the way of accommodating an external stimulus also plays an important role in circadian oscillations. In this regard, there is a different feature in the CCRNs of Drosophila and mammals (Fig. 2 A). A light stimulus activates the transcription of clock genes in mammals while it induces the degradation of clock proteins in Drosophila (8,17). Light acts in multiple ways in plants. For instance, in Arabidopsis, light induces the transcription of CCA1 and LHY through PHYs, CRYs, and ELF3 (8). Light also inhibits ZTL, which induces the degradation of TOC1. As TOC1 induces the transcription of CCA1 and LHY, light stimuli seem to play a similar role in the two regulatory mechanisms. In this respect, we assumed that the main effect of light is to induce gene transcription in the plant CCRN model.
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To examine the role of light in determining the entrainment time, we constructed mathematical models of Drosophila and mammals. The two mathematical models are same except the regulatory mechanism of light (gene transcription for mammals and protein degradation for Drosophila) (see Fig. 2 A and Supplementary Material). We applied various lengths of constant light stimuli to the two CCRN models after we made them entrained to the 12:12 LD cycle, and measured the time for each CCRN to entrain to the 12:12 LD cycle. The simulation results in Fig. 2 D show that the mammalian CCRN model is more slowly entrained to a light stimulus than the CCRN model of Drosophila, which is in accord with experimental results (5,6,18). Hence, we found that the protein degradation induced by light expedites the entrainment compared to the gene transcription. By comparing the simulation results of the MP model and the mammalian CCRN model, we also found that the different entrainment features are induced by the different interacting points of light (see Fig. 2).
We were intrigued why the response of a plant (and Drosophila) circadian clock to light changes is relatively fast compared to that of a mammalian circadian clock and explored this question through extensive computer simulations. Among the various factors determining the entrainment feature to light changes, we found that the topological structure of a CCRN, the regulatory mechanism induced by light, and the interacting point of light are important factors. In particular, the additional positive feedback in the coupled feedback structure seems to be responsible for the relatively slow entrainment in mammals compared to plants while the protein degradation induced by light in Drosophila might also contribute to its relatively fast entrainment. Investigating the relationship between the behavioral rhythms (e.g., overcoming jet lag) and the important factors we found in the entrainment of molecular clocks remains as a future study.
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FOOTNOTES |
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Submitted on February 13, 2007; accepted for publication April 12, 2007.
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REFERENCES |
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