Intracellular and intercellular processes determine robustness of the circadian clock

Circadian clocks are present in most organisms and provide an adaptive mechanism to coordinate physiology and behavior with predictable changes in the environment. Genetic, biochemical, and cellular experiments have identified more than a dozen component genes and a signal transduction pathway that support cell-autonomous, circadian clock function. One of the hallmarks of biological clocks is their ability to reset to relevant stimuli while ignoring most others. We review recent results showing intracellular and intercellular mechanisms that convey this robust timekeeping to a variety of circadian cell types.     

Plant cell responses to cold are all about timing

Changes in temperature present the cells of plants with particular challenges. Fortunately, many changes in temperature can be anticipated due to the rhythms of day/night and the seasons. To anticipate changes in the environment most organisms have a circadian clock to optimize daily and seasonal timing of gene expression, metabolism, physiology and cell biology. Circadian clocks comprised positive and negative feedback loops which ensure an internal period of approximately 24 hours. We describe the role of the circadian clock in modulating cellular cold signalling networks to prepare the cell for the onset of winter.     

Are Circadian Rhythms the Code of Hypothalamic-Immune Communication? Insights from Natural Killer Cells

Circadian rhythms in physiology and behavior are ultimately regulated at the hypothalamic level by the suprachiasmatic nuclei (SCN). This central oscillator transduces photic information to the cellular clocks in the periphery through the autonomic nervous system and the neuroendocrine system. The fact that these two systems have been shown to modulate leukocyte physiology supports the concept that the circadian component is an important aspect of hypothalamic-immune communication. Circadian disruption has been linked to immune dysregulation, and recent reports suggest that several circadian clock genes, in addition to their time-keeping role, are involved in the immune response. In this overview, we summarize the findings demonstrating that Natural Killer (NK) cell function is under circadian control. Special issue article in honor of George Fink.     

Cellular and biochemical mechanisms underlying circadian rhythms in vertebrates

Circadian clocks organize neural processes, such as motor activities, into near 24-hour oscillations and adaptively synchronize these rhythms to the solar cycle. Recently, the first mammalian clock genes have been found. Unpredicted diversity in signaling pathways and clock-controlled gating of signals that modulate timekeeping has been discovered. A diffusible clock output has been found to control some behavioral rhythms. Consensus is emerging that circadian mechanisms are conserved across phylogeny, but that mammals have developed a great complexity of controls.     

Insect circadian clock outputs

Insects display an impressive variety of daily rhythms, which are most evident in their behaviour. Circadian timekeeping systems that generate these daily rhythms of physiology and behaviour all involve three interacting elements: the timekeeper itself (i.e. the clock), inputs to the clock through which it entrains and otherwise responds to environmental cues such as light and temperature, and outputs from the clock through which it imposes daily rhythms on various physiological and behavioural parameters. In insects, as in other animals, cellular clocks are embodied in clock neurons capable of sustained autonomous circadian rhythmicity, and those clock neurons are organized into clock circuits. Drosophila flies spend their entire lives in small areas near the ground, and use their circadian brain clock to regulate daily rhythms of rest and activity, so as to organize their behaviour appropriately to the daily rhythms of their local environment. Migratory locusts and butterflies, on the other hand, spend substantial portions of their lives high up in the air migrating long distances (sometimes thousands of miles) and use their circadian brain clocks to provide time-compensation to their sun-compass navigational systems. Interestingly, however, there appear to be substantial similarities in the cellular and network mechanisms that underlie circadian outputs in all insects.     

Functional Analysis of Casein Kinase 1 in a Minimal Circadian System

The Earth’s rotation has driven the evolution of cellular circadian clocks to facilitate anticipation of the solar cycle. Some evidence for timekeeping mechanism conserved from early unicellular life through to modern organisms was recently identified, but the components of this oscillator are currently unknown. Although very few clock components appear to be shared across higher species, Casein Kinase 1 (CK1) is known to affect timekeeping across metazoans and fungi, but has not previously been implicated in the circadian clock in the plant kingdom. We now show that modulation of CK1 function lengthens circadian rhythms in Ostreococcus tauri , a unicellular marine algal species at the base of the green lineage, separated from humans by ~1.5 billion years of evolution. CK1 contributes to timekeeping in a phase-dependent manner, indicating clock-mediated gating of CK1 activity. Label-free proteomic analyses upon overexpression as well as inhibition revealed CK1-responsive phosphorylation events on a set of target proteins, including highly conserved potentially clock-relevant cellular regulator proteins. These results have major implications for our understanding of cellular timekeeping and can inform future studies in any circadian organism.     

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.     

Ageing in relation to skeletal muscle dysfunction: redox homoeostasis to regulation of gene expression

Ageing is associated with a progressive loss of skeletal muscle mass, quality and function—sarcopenia, associated with reduced independence and quality of life in older generations. A better understanding of the mechanisms, both genetic and epigenetic, underlying this process would help develop therapeutic interventions to prevent, slow down or reverse muscle wasting associated with ageing. Currently, exercise is the only known effective intervention to delay the progression of sarcopenia. The cellular responses that occur in muscle fibres following exercise provide valuable clues to the molecular mechanisms regulating muscle homoeostasis and potentially the progression of sarcopenia. Redox signalling, as a result of endogenous generation of ROS/RNS in response to muscle contractions, has been identified as a crucial regulator for the adaptive responses to exercise, highlighting the redox environment as a potentially core therapeutic approach to maintain muscle homoeostasis during ageing. Further novel and attractive candidates include the manipulation of microRNA expression. MicroRNAs are potent gene regulators involved in the control of healthy and disease-associated biological processes and their therapeutic potential has been researched in the context of various disorders, including ageing-associated muscle wasting. Finally, we discuss the impact of the circadian clock on the regulation of gene expression in skeletal muscle and whether disruption of the peripheral muscle clock affects sarcopenia and altered responses to exercise. Interventions that include modifying altered redox signalling with age and incorporating genetic mechanisms such as circadian- and microRNA-based gene regulation, may offer potential effective treatments against age-associated sarcopenia.     

MAP kinases in the mammalian circadian system--key regulators of clock function

Over the past 7 years, there has been spectacular progress in our understanding of the molecular basis of the circadian pacemaker in many species, from yeast to mammals. However, the biochemical signalling mechanisms that underpin synchronization of the clock to environmental cues are still poorly understood. Recently, attention has been focused on the role of mitogen-activated protein (MAP) kinase in biological timekeeping. It has been proposed that signal transduction via the MAP kinase cascades allows environmental information to be assimilated intracellularly within the circadian clock to produce changes in the phasing of clock gene expression, which, in turn, underlies clock-controlled phase-resetting of biological rhythms. This review examines the evidence for MAP kinase, particularly extracellular regulated kinases 1/2, involvement in the circadian clock and looks at the putative upstream regulators and downstream substrates of this signalling system.     

Modulation of environmental responses of plants by circadian clocks

Circadian clocks are signalling networks that enhance an organism's relationship with the rhythmic environment. The plant circadian clock modulates a wide range of physiological and biochemical events, such as stomatal and organ movements, photosynthesis and induction of flowering. Environmental signals regulate the phase and period of the plant circadian clock, which results in an approximate synchronization of clock outputs with external events. One of the consequences of circadian control is that stimuli of the same strength applied at different times of the day can result in responses of different intensities. This is known as 'gating'. Gating of a signal may allow plants to better process and react to the wide range and intensities of environmental signals to which they are constantly subjected. Light signalling, stomatal movements and low-temperature responses are examples of signalling pathways that are gated by the circadian clock. In this review, we describe the many levels at which the circadian clock interacts with responses to the environment. We discuss how environmental rhythms of temperature and light intensity entrain the circadian clock, how photoperiodism may be regulated by the relationship between environmental rhythms and the phasing of clock outputs, and how gating modulates the sensitivity of the clock and other responses to environmental and physiological signals. Finally, we describe evidence that the circadian clock can increase plant fitness.