The current state and problems of circadian clock studies in cyanobacteria

Circadian rhythms have been observed in innumerable physiological processes in most of organisms. Recent molecular and genetic studies on circadian clocks in many organisms have identified and characterized several molecular regulatory factors that contribute to generation of such rhythms. The cyanobacterium is the simplest organism known to harbor circadian clocks, and it has become one of most successful model organisms for circadian biology. In this review, we will briefly summarize physiological observations and consideration of circadian rhythms in cyanobacteria, molecular genetics of the clock using Synechococcus, and current knowledge of the input and output pathways that support the cellular circadian system. Finally, we will document some current problems in the studies on the cyanobacterial circadian clock.     

Interactions of circadian clock genes with the hallmarks of cancer

The molecular machinery of the circadian clock regulates the expression of many genes and processes in the organism, allowing the adaptation of cellular activities to the daily light-dark cycles.Disruption of the circadian rhythm can lead to various pathologies, including cancer. Thus, disturbance of the normal circadian clock at both genetic and environmental levels has been described as an independent risk factor for cancer. In addition, researchers have proposed that circadian genes may have a tissue-dependent and/or context-dependent role in tumorigenesis and may function both as tumor suppressors and oncogenes.Finally, circadian clock core genes may trigger or at least be involved in different hallmarks of cancer. Hence, expanding the knowledge of the molecular basis of the circadian clock would be helpful to identify new prognostic markers of tumorigenesis and potential therapeutic targets.     

Melatonin in the multi-oscillatory mammalian circadian world

In mammals, the complex interaction of neural, hormonal, and behavioral outputs from the suprachiasmatic nucleus (SCN) drives circadian expression of events, either directly or through coordination of the timing of peripheral oscillators. Melatonin, one of the endocrine output signals of the clock, provides the organism with circadian information and can be considered as an endogenous synchronizer, able to stabilize and reinforce circadian rhythms and to maintain their mutual phase-relationship at the different levels of the circadian network. Moreover, exogenous melatonin, through an action on the circadian clock, affects all levels of the circadian network. The molecular mechanisms underlying this chronobiotic effect have also been investigated in rats. REV-ERB alpha seems to be the initial molecular target.     

Melatonin in the multi‐oscillatory mammalian circadian world

In mammals, the complex interaction of neural, hormonal, and behavioral outputs from the suprachiasmatic nucleus (SCN) drives circadian expression of events, either directly or through coordination of the timing of peripheral oscillators. Melatonin, one of the endocrine output signals of the clock, provides the organism with circadian information and can be considered as an endogenous synchronizer, able to stabilize and reinforce circadian rhythms and to maintain their mutual phase‐relationship at the different levels of the circadian network. Moreover, exogenous melatonin, through an action on the circadian clock, affects all levels of the circadian network. The molecular mechanisms underlying this chronobiotic effect have also been investigated in rats. REV‐ERB α seems to be the initial molecular target.     

Circadian rhythms in plants: a millennial view

Circadian rhythms are endogenous rhythms with periods of approximately 24 h. These rhythms are widespread both within any given organism and among diverse taxa. As genetic and molecular biological studies, primarily in a subset of model organisms, have begun to identify the components of circadian systems, there is optimism that we will soon achieve a detailed molecular understanding of circadian timing mechanisms. Although plants have provided many examples of rhythmic outputs, and our understanding of photoreceptors of circadian input pathways is well-advanced, plants have lagged behind other groups of organisms in the identification of components of the central circadian oscillator. However, there are now a number of promising candidates for components of plant circadian clocks, and it seems probable that we will soon know the details of a plant central oscillator. Moreover, there is also accumulating evidence that plants and other organisms house multiple circadian clocks, both in different tissues and, quite probably, within individual cells. This provides an unanticipated level of complexity with the potential for interaction among these multiple oscillators.     

Unraveling the mechanisms of the vertebrate circadian clock: zebrafish may light the way

Most organisms display oscillations of approximately 24 hours in their physiology. In higher organisms, these circadian oscillations in biochemical and physiological processes ultimately control complex behavioral rhythms that allow an organism to thrive in its natural habitat. Daily and seasonal light cycles are mainly responsible for keeping the circadian system properly aligned with the environment. The molecular mechanisms responsible for the control of the circadian clock have been explored in a number of systems. Interestingly, the circadian oscillations that are responsive to environmental stimuli are present very early during development. This review focuses on the advantages of using the zebrafish to study the development of the vertebrate circadian system and light-dependent signaling to the clock.     

Circadian systems: different levels of complexity.

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 specific circadian qualities but not necessarily to the generation of circadian rhythmicity. For a full appreciation of the circadian programme, the results from different levels of the system eventually have to be put into the context of the organism as a whole and its specific 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 different levels of the circadian system.     

Chlamydomonas reinhardtii as a unicellular model for circadian rhythm analysis

Chlamydomonas reinhardtii has been used as an experimental model organism for circadian rhythm research for more than 30 yr. Some of the physiological rhythms of this alga are well established, and several clock mutants have been isolated. The cloning of clock genes from these mutant strains by positional cloning is under way and should give new insights into the mechanism of the circadian clock. In a spectacular space experiment, the question of the existence of an endogenous clock vs. an exogenous mechanism has been studied in this organism. With the emergence of molecular analysis of circadian rhythms in plants in 1985, a circadian gene expression pattern of several nuclear and chloroplast genes was detected. Evidence is now accumulating that shows circadian control at the translational level. In addition, the gating of the cell cycle by the circadian clock has been analyzed. This review focuses on the different aspects of circadian rhythm research in C. reinhardtii over the past 30 yr. The suitability of Chlamydomonas as a model system in chronobiology research and the adaptive significance of the observed rhythms will be discussed.     

Circadian rhythms: from gene expression to behavior

Circadian rhythms regulate the functions of living systems at virtually every level of organization, from molecule to organism. In the past year, our understanding of the cellular and molecular processes involved in the generation and regulation of circadian rhythms has advanced considerably. New in vitro model systems for studying circadian oscillators have been developed, a potential regulatory role for cellular immediate-early genes in circadian behavior has been discovered, critical periods for macromolecular synthesis for progression of the circadian clock through its cycle have been defined, and studies of the Drosophila period gene have offered new insight into the clock mechanism. These findings are of particular interest because independent approaches using vertebrates, mollusks and Drosophila all point to a common theme that involves the expression of 'clock proteins' as the basis of the timing mechanism.     

Insect photoperiodism and circadian clocks: models and mechanisms

Photoperiodic clocks allow organisms to predict the coming season. In insects, the seasonal adaptive response mainly takes the form of diapause. The extensively studied photoperiodic clock in insects was primarily characterized by a "black-box" approach, resulting in numerous cybernetic models. This is in contrast with the circadian clock, which has been dissected pragmatically at the molecular level, particularly in Drosophila. Unfortunately, Drosophila melanogaster, the favorite model organism for circadian studies, does not demonstrate a pronounced seasonal response, and consequently molecular analysis has not progressed in this area. In the current article, the authors explore different ways in which identified molecular components of the circadian pacemaker may play a role in photoperiodism. Future progress in understanding the Drosophila circadian pacemaker, particularly as further output components are identified, may provide a direct link between the clock and photoperiodism. In addition, with improved molecular tools, it is now possible to turn to other insects that have a more dramatic photoperiodic response.     

Chlamydomonas reinhardtii as a unicellular model for circadian rhythm analysis

Chlamydomonas reinhardtii has been used as an experimental model organism for circadian rhythm research for more than 30 yr. Some of the physiological rhythms of this alga are well established, and several clock mutants have been isolated. The cloning of clock genes from these mutant strains by positional cloning is under way and should give new insights into the mechanism of the circadian clock. In a spectacular space experiment, the question of the existence of an endogenous clock vs. an exogenous mechanism has been studied in this organism. With the emergence of molecular analysis of circadian rhythms in plants in 1985, a circadian gene expression pattern of several nuclear and chloroplast genes was detected. Evidence is now accumulating that shows circadian control at the translational level. In addition, the gating of the cell cycle by the circadian clock has been analyzed. This review focuses on the different aspects of circadian rhythm research in C. reinhardtii over the past 30 yr. The suitability of Chlamydomonas as a model system in chronobiology research and the adaptive significance of the observed rhythms will be discussed.     

Clocks not winding down: unravelling circadian networks

An intrinsic clock enables an organism to anticipate environmental changes and use energy sources more efficiently, thereby conferring an adaptive advantage. Having an intrinsic clock to orchestrate rhythms is also important for human health. The use of systems biology approaches has advanced our understanding of mechanistic features of circadian oscillators over the past decade. The field is now in a position to develop a multiscale view of circadian systems, from the molecular level to the intact organism, and to apply this information for the development of new therapeutic strategies or for enhancing agricultural productivity in crops.     

Melatonin in the circadian system

In Mammals, the master circadian clock is located in the suprachiasmatic nuclei of the hypothalamus. This clock is synchronized with the astronomical time, essentially by the light/dark cycle. The different zeitgebers studied act on the Per1 and/or Per2 genes from the main molecular loop which initiates the circadian oscillations. Once synchronized with the environment, circadian oscillations are distributed through the organism by efferent signals, and the complex interaction of neural, hormonal and behavioural outputs from the circadian clock drive circadian expression of events, either directly or through coordination of the timing of peripheral oscillators. Melatonin, one of the endocrine output signals of the clock, provides the organism with circadian information, and can be considered as an endogenous synchronizer. Melatonin receptors are present in the suprachiasmatic nuclei which allows the hormone to feed back on the clock. To day, the physiological role of this peculiar feed-back has not yet been established. However, the presence of these receptors indicates that through an action on the circadian clock, exogenous melatonin can affect all levels of the circadian network and its capacity to entrain circadian rhythms to 24 h has been demonstrated. Melatonin is thus a zeitgeber. However, surprisingly, and different from the action mechanism of other zeitgebers on the clock, the chronobiotic effect of melatonin does not implicate Per1 and/or Per2. Rather, Rev-erb alpha could be the link between the physiological action of melatonin and the core of the molecular circadian clock.     

The circadian clock system in the mammalian retina

Daily rhythms are a ubiquitous feature of living systems. Generally, these rhythms are not just passive consequences of cyclic fluctuations in the environment, but instead originate within the organism. In mammals, including humans, the master pacemaker controlling 24-hour rhythms is localized in the suprachiasmatic nuclei of the hypothalamus. This circadian clock is responsible for the temporal organization of a wide variety of functions, ranging from sleep and food intake, to physiological measures such as body temperature, heart rate and hormone release. The retinal circadian clock was the first extra-SCN circadian oscillator to be discovered in mammals and several studies have now demonstrated that many of the physiological, cellular and molecular rhythms that are present within the retina are under the control of a retinal circadian clock, or more likely a network of hierarchically organized circadian clocks that are present within this tissue. BioEssays 30:624-633, 2008. (c) 2008 Wiley Periodicals, Inc.     

Chlamydomonas reinhardtii as a new model system for studying the molecular basis of the circadian clock

The genome of the unicellular green alga Chlamydomonas reinhardtii has both plant-like and animal-like genes. It is of interest to know which types of clock genes this alga has. Recent forward and reverse genetic studies have revealed that its clock has both plant-like and algal clock components. In addition, since C. reinhardtii is a useful model organism also called "green yeast", the identification of clock genes will make C. reinhardtii a powerful model for studying the molecular basis of the eukaryotic circadian clock. In this review, we describe our forward genetic approach in C. reinhardtii and discuss some recent findings about its circadian clock.     

Entrainment of Drosophila circadian rhythms by temperature cycles

Sleep and Biological Rhythms - The fruit fly, Drosophila melanogaster, has been a good organism for elucidating the molecular and cellular bases of circadian behavioral rhythms. The fly shows a...