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Results for “Circadian Clocks”

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At least 19 recordsLinked to original sources

PubMed2003

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.

Adaptation, Physiological↗

PubMed2000

Molecular mechanism and cellular distribution of insect circadian clocks.

Circadian clocks are endogenous timing mechanisms that control molecular, cellular, physiological, and behavioral rhythms in all organisms from unicellulars to humans. Circadian rhythms influence many aspects of insect biology, finetuning life functions to the light and temperature cycles associated with the solar day. Genetic studies in the fruit fly Drosophila melanogaster have led to the cloning and characterization of several genes involved in the mechanism of the circadian clock. Periodic transcription and translation of these clock genes form the basis of a molecular feedback loop that has a "circa" 24-hour period. Rhythmic expression of clock genes in specific brain neurons appears to control behavioral rhythms in adult flies. However, clock genes are also expressed in other tissues, both within and outside of the nervous system. These observations prompted chronobiologists to investigate whether nonneural tissues possess intrinsic circadian clocks, what role they may be playing, and what the relationships are between clocks in the nervous system and those in peripheral tissues. Answers to those questions are providing important insights into the overall organization of the circadian system in insects.

Animals↗

PubMed2005

A model for the Neurospora circadian clock.

Circadian clocks are important biological oscillators that generally involve two feedback loops. Here, we propose a new model for the Neurospora crassa circadian clock. First, we model its main negative feedback loop, including only experimentally well-documented reactions, the transcriptional activation of frequency (frq) by the white-collar complex (WCC), and the post-transcriptional dimerization of FRQ with WCC. This main loop is sufficient for oscillations and a similar one lies at the core of almost all known circadian clocks. Second, the model is refined to include the less characterized enhancement of white-collar 1 (WC-1) protein synthesis by FRQ, the positive second feedback loop. Numerical testing of different hypotheses led us to propose that the synthesis of WC-1 is enhanced by FRQ monomers and repressed by FRQ dimers. We demonstrate that this second loop contributes significantly to the robustness of the oscillator period against parameter variation. A phase response curve to light pulses is also computed and agrees well with experiments. On a general level, our results show that explicit time delays are not required for sustained oscillations but that it is crucial to take into account mRNA dynamics and protein-protein interactions.

Biological Clocks↗

PubMed2004

Protein kinase G type II is required for night-to-day progression of the mammalian circadian clock.

Circadian clocks comprise a cyclic series of dynamic cellular states, characterized by the changing availability of substrates that alter clock time when activated. To determine whether circadian clocks, like the cell cycle, exhibit regulation by key phosphorylation events, we examined endogenous kinase regulation of timekeeping in the mammalian suprachiasmatic nucleus (SCN). Short-term inhibition of PKG-II but not PKG-Ibeta using antisense oligodeoxynucleotides delayed rhythms of electrical activity and Bmal1 mRNA. Phase resetting was rapid and dynamic; inhibition of PKG-II forced repetition of the last 3.5 hr of the cycle. Chronic inhibition of PKG-II disrupted electrical activity rhythms and tonically increased Bmal1 mRNA. PKG-II-like immunoreactivity was detected after coimmunoprecipitation with CLOCK, and CLOCK was phosphorylated in the presence of active PKG-II. PKG-II activation may define a critical control point for temporal progression into the daytime domain by acting on the positive arm of the transcriptional/translational feedback loop.

Animals↗

PubMed1998

A neuronal ryanodine receptor mediates light-induced phase delays of the circadian clock.

Circadian clocks are complex biochemical systems that cycle with a period of approximately 24 hours. They integrate temporal information regarding phasing of the solar cycle, and adjust their phase so as to synchronize an organism's internal state to the local environmental day and night. Nocturnal light is the dominant regulator of this entrainment. In mammals, information about nocturnal light is transmitted by glutamate released from retinal projections to the circadian clock in the suprachiasmatic nucleus of the hypothalamus. Clock resetting requires the activation of ionotropic glutamate receptors, which mediate Ca2+ influx. The response induced by such activation depends on the clock's temporal state: during early night it delays the clock phase, whereas in late night the clock phase is advanced. To investigate this differential response, we sought signalling elements that contribute solely to phase delay. We analysed intracellular calcium-channel ryanodine receptors, which mediate coupled Ca2+ signalling. Depletion of intracellular Ca2+ stores during early night blocked the effects of glutamate. Activators of ryanodine receptors induced phase resetting only in early night; inhibitors selectively blocked delays induced by light and glutamate. These findings implicate the release of intracellular Ca2+ through ryanodine receptors in the light-induced phase delay of the circadian clock restricted to the early night.

Animals↗

PubMed2005

At the pulse of time: protein interactions determine the pace of circadian clocks.

Circadian clocks, internal timekeepers that generate a daily rhythmicity, help organisms to be prepared for periodic environmental changes of light and temperature. These molecular clocks are transcriptional feedback loops that generate 24-h oscillations in the abundance of clock proteins. For the maintenance of this rhythm inside the core clockwork and for its transmission to downstream genes the clock proteins additionally rely on post-transcriptional and post-translational mechanisms. Thus clock proteins engage in a variety of interactions with DNA, RNA and other proteins. Based on the model organisms Drosophila melanogaster and Arabidopsis thaliana molecular principles of circadian clocks are discussed in this review.

Animals↗

PubMed1998

Glyceraldehyde-3-phosphate dehydrogenase is regulated on a daily basis by the circadian clock.

Circadian clocks function to govern a wide range of rhythmic activities in organisms. An integral part of rhythmicity is the daily control of target genes by the clock. Here we describe the sequence and analysis of a novel clock-controlled gene, ccg-7, showing similarity to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a glycolytic enzyme widely used as a constitutive control in a variety of systems. That ccg-7 encodes GAPDH was confirmed by demonstrating that in vitro synthesized CCG-7 possesses GAPDH activity. Rhythms in both ccg-7 mRNA accumulation and CCG-7 (GAPDH) activity are observed in a clock wild-type strain where the peak in GAPDH activity lags several hours behind the peak in ccg-7 mRNA accumulation in the late night. Together with our previous observation that ccg-7 mRNA is not developmentally regulated, we show that ccg-7 is not induced by environmental stresses such as glucose or nitrogen deprivation (which also trigger development), heat shock, or osmotic stress. Thus, the finding that GAPDH is clock-regulated points to a specific role for the circadian clock in controlling aspects of general metabolism and provides evidence for circadian regulation of a gene found in most living organisms.

Amino Acid Sequence↗

PubMed2003

Molecular mechanism of mammalian circadian clock.

Circadian rhythms in behaviors and physiological phenomena of plants and animals have long been well known, but the frameworks of the molecular mechanism of circadian clocks have become clearer only within the last decade. A transcription-translation feedback loop has been shown to be an essential component of the clock, and this mechanism seems to be conserved over a wide range of species. The transcriptional activation by a Clock:Bmal1 heterodimer and the inhibition by Cryptochrome and Period are believed to provide the framework of the feedback loop in mammals. Posttranslational modifications such as phosphorylation, nuclear entry and degradation have also been demonstrated to be necessary for the oscillation. Complex auxiliary loops have also been found, and these are thought to contribute to the stabilization of the feedback loop. The molecular mechanisms by which the circadian clock is adjusted to external conditions such as daily light-dark cycles, and by which the oscillation of the feedback loop is transferred to the peripheral organs are also discussed.

Animals↗

PubMed2006

The molecular basis of temperature compensation in the Arabidopsis circadian clock.

Circadian clocks maintain robust and accurate timing over a broad range of physiological temperatures, a characteristic termed temperature compensation. In Arabidopsis thaliana, ambient temperature affects the rhythmic accumulation of transcripts encoding the clock components TIMING OF CAB EXPRESSION1 (TOC1), GIGANTEA (GI), and the partially redundant genes CIRCADIAN CLOCK ASSOCIATED1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY). The amplitude and peak levels increase for TOC1 and GI RNA rhythms as the temperature increases (from 17 to 27 degrees C), whereas they decrease for LHY. However, as temperatures decrease (from 17 to 12 degrees C), CCA1 and LHY RNA rhythms increase in amplitude and peak expression level. At 27 degrees C, a dynamic balance between GI and LHY allows temperature compensation in wild-type plants, but circadian function is impaired in lhy and gi mutant plants. However, at 12 degrees C, CCA1 has more effect on the buffering mechanism than LHY, as the cca1 and gi mutations impair circadian rhythms more than lhy at the lower temperature. At 17 degrees C, GI is apparently dispensable for free-running circadian rhythms, although partial GI function can affect circadian period. Numerical simulations using the interlocking-loop model show that balancing LHY/CCA1 function against GI and other evening-expressed genes can largely account for temperature compensation in wild-type plants and the temperature-specific phenotypes of gi mutants.

Acclimatization↗

PubMed1991

Regularly scheduled voluntary exercise synchronizes the mouse circadian clock.

Circadian rhythm entrainment has long been thought to depend exclusively on periodic cues in the external environment. However, evidence now suggests that appropriately timed vigorous activity may also phase shift the circadian clock. Previously it was not known whether levels of exercise/activity associated with spontaneous behavior provided sufficient feedback to phase shift or synchronize circadian rhythms. The present study investigated this issue by monitoring the sleep-wake, drinking, and wheel-running circadian rhythms of mice (Mus musculus) during unrestricted access to running wheels and when free wheel rotation was limited to either 12- or 6-h intervals with a fixed period of 24 h. Wheel rotation was controlled remotely. Mice spontaneously ran in wheels during scheduled access, and free-running sleep-wake and drinking circadian rhythms became entrained to scheduled exercise in 11 of 15 animals. However, steady-state entrainment was achieved only when exercise commenced several hours into the subjective night. The temporal placement of running during entrainment was related (r = 0.7003, P less than 0.02) to free-running period before entrainment. Mice with a free-running period less than 23.0 h did not entrain but exhibited relative coordination between free-running variables and the wheel availability schedule. Thus the circadian timekeeping system responds to temporal feedback arising from the timing of volitional exercise/activity, suggesting that the biological clock not only is responsive to periodic geophysical events in the external environment but also derives physiological feedback from the spontaneous activity behaviors of the organism.

Animals↗

PubMed1998

Phytochromes and cryptochromes in the entrainment of the Arabidopsis circadian clock.

Circadian clocks are synchronized by environmental cues such as light. Photoreceptor-deficient Arabidopsis thaliana mutants were used to measure the effect of light fluence rate on circadian period in plants. Phytochrome B is the primary high-intensity red light photoreceptor for circadian control, and phytochrome A acts under low-intensity red light. Cryptochrome 1 and phytochrome A both act to transmit low-fluence blue light to the clock. Cryptochrome 1 mediates high-intensity blue light signals for period length control. The presence of cryptochromes in both plants and animals suggests that circadian input pathways have been conserved throughout evolution.

Arabidopsis↗

PubMed2004

Real-time imaging reveals spatiotemporal dynamics of cellular circadian clocks.

Circadian clocks have been localized to discrete sites within the nervous systems of several organisms, and in mammals to the suprachiasmatic nucleus (SCN) in the anterior hypothalamus. The clock in the SCN is composed of multiple autonomous single-cell oscillators, and new studies now allow an unprecedented look at their oscillatory activities over repeated cycles in tissue slices in vitro. Initial data reinforce the importance of intercellular membrane events for constructing a functional and reliable tissue pacemaker.

Animals↗

PubMed1999

The mPer2 gene encodes a functional component of the mammalian circadian clock.

Circadian rhythms are driven by endogenous biological clocks that regulate many biochemical, physiological and behavioural processes in a wide range of life forms. In mammals, there is a master circadian clock in the suprachiasmatic nucleus of the anterior hypothalamus. Three putative mammalian homologues (mPer1, mPer2 and mPer3) of the Drosophila circadian clock gene period (per) have been identified. The mPer genes share a conserved PAS domain (a dimerization domain found in Per, Arnt and Sim) and show a circadian expression pattern in the suprachiasmatic nucleus. To assess the in vivo function of mPer2, we generated and characterized a deletion mutation in the PAS domain of the mouse mPer2 gene. Here we show that mice homozygous for this mutation display a shorter circadian period followed by a loss of circadian rhythmicity in constant darkness. The mutation also diminishes the oscillating expression of both mPer1 and mPer2 in the suprachiasmatic nucleus, indicating that mPer2 may regulate mPer1 in vivo. These data provide evidence that an mPer gene functions in the circadian clock, and define mPer2 as a component of the mammalian circadian oscillator.

Animals↗

PubMed2004

Stochastic simulation of the mammalian circadian clock.

Circadian (nearly 24-h) clocks are remarkably accurate at timing biological events despite the randomness of their biochemical reactions. Here we examine the causes of their immunity to molecular noise in the context of a detailed stochastic mathematical model of the mammalian circadian clock. This stochastic model is a direct generalization of the deterministic mammalian circadian clock model previously developed. A feature of that model is that it completely specifies all molecular reactions, leaving no ambiguity in the formulation of a stochastic version of the model. With parameters based on experimental data concerning clock protein concentrations within a cell, we find accurate circadian rhythms in our model only when promoter interaction occurs on the time scale of seconds. As the model is scaled up by proportionally increasing the numbers of molecules of all species and the reaction rates with the promoter, the observed variability scales as 1/n(0.5), where n is the number of molecules of any species. Our results show that gene duplication increases robustness by providing more promoters with which the transcription factors of the model can interact. Although PER2 mutants were not rhythmic in the deterministic version of this model, they are rhythmic in the stochastic version.

Animals↗

PubMedDate not supplied

A role for casein kinase 2alpha in the Drosophila circadian clock.

Circadian clocks drive rhythmic behaviour in animals and are regulated by transcriptional feedback loops. For example, the Drosophila proteins Clock (Clk) and Cycle (Cyc) activate transcription of period (per) and timeless (tim). Per and Tim then associate, translocate to the nucleus, and repress the activity of Clk and Cyc. However, post-translational modifications are also critical to proper timing. Per and Tim undergo rhythmic changes in phosphorylation, and evidence supports roles for two kinases in this process: Doubletime (Dbt) phosphorylates Per, whereas Shaggy (Sgg) phosphorylates Tim. Yet Sgg and Dbt often require a phosphoserine in their target site, and analysis of Per phosphorylation in dbt mutants suggests a role for other kinases. Here we show that the catalytic subunit of Drosophila casein kinase 2 (CK2alpha) is expressed predominantly in the cytoplasm of key circadian pacemaker neurons. CK2alpha mutant flies show lengthened circadian period, decreased CK2 activity, and delayed nuclear entry of Per. These effects are probably direct, as CK2alpha specifically phosphorylates Per in vitro. We propose that CK2 is an evolutionary link between the divergent circadian systems of animals, plants and fungi.

Active Transport, Cell Nucleus↗

PubMed1999

Oscillation and light induction of timeless mRNA in the mammalian circadian clock.

Circadian rhythms in Drosophila melanogaster depend on a molecular feedback loop generated by oscillating products of the period (per) and timeless (tim) genes. In mammals, three per homologs are cyclically expressed in the suprachiasmatic nucleus (SCN), site of the circadian clock, and two of these, mPer1 and mPer2, are induced in response to light. Although this light response distinguishes the mammalian clock from its Drosophila counterpart, overall regulation, including homologous transcriptional activators, appears to be similar. Thus, the basic mechanisms used to generate circadian timing have been conserved. However, contrary to expectations, the recently isolated mammalian tim homolog was reported not to cycle. In this study, we examined mRNA levels of the same tim homolog using a different probe. We observed a significant (approximately threefold) diurnal variation in mTim expression within mouse SCN using two independent methods. Peak levels were evident at the day-to-night transition in light-entrained animals, and the oscillation persisted on the second day in constant conditions. Furthermore, light pulses known to induce phase delays caused significant elevation in mTim mRNA. In contrast, phase-advancing light pulses did not affect mTim levels. The mTim expression profile and the response to nocturnal light are similar to mPer2 and are delayed compared with mPer1. We conclude that temporal ordering of mTim and mPer2 parallels that of their fly homologs. We predict that mTIM may be the preferred functional partner for mPER2 and that expression of mTim and mPer2 may, in fact, be driven by mPER1.

Animals↗

PubMed2003

A suite of photoreceptors entrains the plant circadian clock.

Circadian rhythms in plants are relatively robust, as they are maintained both in constant light of high fluence rates and in darkness. Plant circadian clocks exhibit the expected modes of photoentrainment, including period modulation by ambient light and phase resetting by brief light pulses. Several of the phytochrome and cryptochrome photoreceptors responsible have been studied in detail. This review concentrates on the resulting patterns of entrainment and on the multiple proposed mechanisms of light input to the circadian oscillator components.

Circadian Rhythm↗

PubMed2000

Short-period mutations of per affect a double-time-dependent step in the Drosophila circadian clock.

Circadian (24 hour) PERIOD (PER) protein oscillation is dependent on the double-time (dbt) gene, a casein kinase Ivarepsilon homolog [1-3]. Without dbt activity, hypophosphorylated PER proteins over-accumulate, indicating that dbt is required for PER phosphorylation and turnover [3,4]. There is evidence of a similar role for casein kinase Ivarepsilon in the mammalian circadian clock [5,6]. We have isolated a new dbt allele, dbt(ar), which causes arrhythmic locomotor activity in homozygous viable adults, as well as molecular arrhythmicity, with constitutively high levels of PER proteins, and low levels of TIMELESS (TIM) proteins. Short-period mutations of per, but not of tim, restore rhythmicity to dbt(ar) flies. This suppression is accompanied by a restoration of PER protein oscillations. Our results suggest that short-period per mutations, and mutations of dbt, affect the same molecular step that controls nuclear PER turnover. We conclude that, in wild-type flies, the previously defined PER'short domain' [7,8] may regulate the activity of DBT on PER.

Amino Acid Sequence↗