A connection between MAPK pathways and circadian clocks

Circadian clocks and mitogen-activated protein kinase (MAPK) signaling pathways are fundamental features of eukaryotic cells. Both pathways provide mechanisms for cells to respond to environmental stimuli, and links between them are known. We recently reported that the circadian clock in Neurospora crassa regulates daily rhythms in accumulation of phosphorylated, and thus active, OS-2 MAPK, a relative of mammalian p38 MAPK, when cells are grown in constant conditions. In the absence of acute stress, rhythmically activated MAPK then signals to downstream effector molecules to regulate rhythmic expression of target genes of the pathway. Clock regulation of MAPK signaling pathways provides a mechanism to coordinately control major groups of genes such that they peak at the appropriate times of day to provide a growth and survival advantage to the organism by anticipating stresses. MAPK pathways are well known for their role in cell proliferation and tumor suppression. New evidence reveals that some mammalian clock components also function as tumor suppressors and rhythms in phospho-MAPK have been observed in higher eukaryotes. Thus, the role of the clock in regulation of the activity of MAPK pathways provides important clues into the function of the circadian clock as a tumor suppressor.     

Feeding and circadian clocks

The mammalian genome encodes at least a dozen of genes directly involved in the regulation of the feedback loops constituting the circadian clock. The circadian system is built up on a multitude of oscillators organized according to a hierarchical model in which neurons of the suprachiasmatic nuclei of the hypothalamus may drive the central circadian clock and all the other somatic cells may possess the molecular components allowing tissues and organs to constitute peripheral clocks. Suprachiasmatic neurons are driving the central circadian clock which is reset by lighting cues captured and integrated by the melanopsin cells of the retina and define the daily rhythms of locomotor activity and associated physiological regulatory pathways like feeding and metabolism. This central clock entrains peripheral clocks which can be synchronized by non-photic environmental cues and uncoupled from the central one depending on the nature and the strength of the circadian signal. The human circadian clock and its functioning in central or peripheral tissues are currently being explored to increase the therapeutic efficacy of timed administration of drugs or radiation, and to offer better advice on lighting and meal timing useful for frequent travelers suffering from jet lag and for night workers' comfort. However, the molecular mechanism driving and coordinating the central and peripheral clocks through a wide range of synchronizers (lighting, feeding, physical or social activities) remains a mystery.     

A model for circadian clocks

An extension of an earlier model simulating the effects of light on the drosophila eclosion rhythm is presented. The effects of variable light intensity are described. This allows not only the simulation of certain experiments not covered by the earlier model, but also it permits an extension of the model to other organisms. By changing only its sensitivity to light the model simulates the phase response curves of certain mammals as well as Aschoff’srule.     

Temperature effects on circadian clocks

Periodic temperature changes represent one of the most effective entraining (Zeitgeber) signals for circadian clocks in many organisms. Different constant temperatures affect the circadian amplitude and ultimately the expression of circadian clocks, while the circadian period length (tau) remains approximately constant (temperature compensation). Experimental results and theoretical models are presented that may serve to explain these effects. After introducing the physico-chemical basis of temperature on enzyme-catalyzed and physiological reactions, and after describing mechanisms for temperature adaptation of physiological reactions to different thermal environments, general effects of temperature on chemical and biological oscillators are described. Kinetic models for circadian clocks and temperature compensation are presented and compared with experimental results. Special attention is given to the question how constant but different temperature levels affect clock amplitude, period length and phase. Influences of single and periodic temperature variations (steps or pulses) on circadian clocks are presented together with models which may explain the resulting phase response curves and entrainment patterns. Because temperature compensation is only one aspect of a general homeostatic mechanism that keeps the circadian period rather constant, the influence of other environmental variables and their relationship to temperature are discussed.     

Adaptive significance of circadian clocks

Circadian clocks are ubiquitous and are found in organisms ranging from bacteria to mammals. This ubiquity of occurrence implies adaptive significance, but to date there has been no rigorous empirical evidence to support this. It is believed that an organism possessing circadian clocks gains fitness advantage in two ways: (i) by synchronizing its behavioral and physiological processes to cyclic environmental factors (extrinsic adaptive value); (ii) by coordinating its internal metabolic processes (intrinsic adaptive value). There is preliminary circumstantial evidence to support both. Several studies using organisms living in constant environments have shown that these organisms possess functional circadian clocks, suggesting that circadian clocks may have some intrinsic adaptive value. Studies to assess the adaptive value of circadian clocks in periodic environments suggest that organisms may have a fitness advantage in those periodic environments, which closely match their own intrinsic periodicity. Furthermore, evidence from organisms living in the wild, selection studies, and studies on latitudinal clines suggest that circadian clocks may have an extrinsic adaptive value as well. In this paper, I have presented several hypotheses for the emergence of circadian clocks and have reviewed some major empirical studies suggesting adaptive significance of circadian clocks.     

The circadian clocks of plants and cyanobacteria

Classical research on the circadian rhythms of plants helped to demonstrate that all living organisms utilize circadian clocks to adapt their day–night cycles and that the clock is the basis for photoperiodic time measurements. Molecular models for the circadian oscillator have now been elucidated in Drosophila, Neurospora, mice and cyanobacteria. All share a similar feedback structure, but key proteins in each of the oscillators are different. A plant clock model has yet to be proposed, but clock mutants of Arabidopsis are expected to reveal key proteins in the mechanism. Here we discuss how a self-sustained oscillation is established in eukaryotic and prokaryotic models, and the polyphyletic evolution of these clock systems.     

Precise circadian clocks in prokaryotic cyanobacteria

Prokaryotic cyanobacteria express robust circadian (daily) rhythms under the control of a timing mechanism that is independent of the cell division cycle. This biological clock orchestrates global regulation of gene expression and controls the timing of cell division. Proteins that may be involved in input pathways have been identified. Mutational screening has identified three clock genes that are organized as a gene cluster. The structure of cyanobacterial clock proteins, their phosphorylation, and regulation is described. A new model for the core clockwork in cyanobacteria proposes that rhythmic changes in the status of the chromosome underlie the rhythms of gene expression. Mixed-strain experiments demonstrate that this timekeeper confers adaptive value when different strains compete against each other.     

Environmental stimulus perception and control of circadian clocks

Circadian rhythms are regulated by clocks located in specific structures of the central nervous system, such as the suprachiasmatic nucleus (SCN) in mammals, and by peripheral oscillators present in various other tissues. Recent discoveries have elucidated the control of central and peripheral clocks by environmental signals. The major synchroniser in animals is light. In mammals, a subset of retinal ganglion cells receive light signals that are transmitted to the SCN via the retinohypothalamic tract. Photoreception is probably elicited by a novel opsin, melanopsin, although cryptochromes may also play a role. These signals feed directly to the SCN master clock, which then provides timing cues to peripheral clocks. In contrast to mammals, peripheral tissues in the fly and in the fish are directly photoreceptive. However, alternative routes exist. Some peripheral clocks in mammals can be specifically entrained in an SCN-independent manner by restricting food during the light period.     

Gene duplication and complex circadian clocks in mammals

The circadian clock arose early in the evolution of life to enable organisms to adapt to the cycle of day and night. Recently, the extent and importance of circadian regulation of behaviour and physiology has come to be more fully realized. Core molecular cogs of circadian oscillators appear to have been largely conserved between such diverse organisms as Drosophila melanogaster and mammals. However, gene duplication events have produced multiple copies of many clock genes in mammals. Recent studies suggest that genome duplication has lead to increased circadian complexity and local tissue regulation. This has important implications for temporal regulation of behaviour via multiple clocks in the central nervous system, and also extends to the local physiology of major body organs and tissues.     

Retinal circadian clocks and control of retinal physiology

Retinas of all classes of vertebrates contain endogenous circadian clocks that control many aspects of retinal physiology, including retinal sensitivity to light, neurohormone synthesis, and cellular events such as rod disk shedding, intracellular signaling pathways, and gene expression. The vertebrate retina is an example of a "peripheral" oscillator that is particularly amenable to study because this tissue is well characterized, the relationships between the various cell types are extensively studied, and many local clock-controlled rhythms are known. Although the existence of a photoreceptor clock is well established in several species, emerging data are consistent with multiple or dual oscillators within the retina that interact to control local physiology. A prominent example is the antiphasic regulation of melaton in and dopamine in photoreceptors and inner retina, respectively. This review focuses on the similarities and differences in the molecular mechanisms of the retinal versus the SCN oscillators, as well as on the expression of core components of the circadian clockwork in retina. Finally, the interactions between the retinal clock(s) and the master clock in the SCN are examined.     

Populations of biochemical oscillators as circadian clocks

Various types of populations of interacting oscillators were analyzed and their synchronization states were determined. One of the systems involving biochemical oscillators was simulated on the computer and the occurence of rhythm splitting was observed. A comparison of its attributes with experimental results on circadian ryhythms showed good agreement. This allows us to distinguish between types of mechanisms held responsible for the splitting phenomenon in the past. The present model also offers a new explanation about the differences of light action on diurnal and nocturnal organisms.