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PubMed2000

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.

Biological Clocks↗
PubMed2005

PSEUDO-RESPONSE REGULATORS, PRR9, PRR7 and PRR5, together play essential roles close to the circadian clock of Arabidopsis thaliana.

In Arabidopsis thaliana, a number of clock-associated protein components have been identified. Among them, CCA1 (CIRCADIAN CLOCK-ASSOCIATED 1)/LHY (LATE ELONGATED HYPOCOTYL) and TOC1 (TIMING OF CAB EXPRESSION 1) are believed to be the essential components of the central oscillator. CCA1 and LHY are homologous and partially redundant Myb-related DNA-binding proteins, whereas TOC1 is a member of a small family of proteins, designated as PSEUDO-RESPONSE REGULATOR. It is also believed that these two different types of clock components form an autoregulatory positive/negative feedback loop at the levels of transcription/translation that generates intrinsic rhythms. Nonetheless, it was not yet certain whether or not other PRR family members (PRR9, PRR7, PRR5 and PRR3) are implicated in clock function per se. Employing a set of prr9, prr7 and prr5 mutant alleles, here we established all possible single, double and triple prr mutants. They were examined extensively by comparing them with each other with regard to their phenotypes of circadian rhythms, photoperiodicity-dependent control of flowering time and photomorphogenic responses to red light during de-etiolation. Notably, the prr9 prr7 prr5 triple lesions in plants resulted in severe phenotypes: (i) arrhythmia in the continuous light conditions, and an anomalous phasing of diurnal oscillation of certain circadian-controlled genes even in the entrained light/dark cycle conditions; (ii) late flowering that was no longer sensitive to the photoperiodicity; and (iii) hyposensitivity (or blind) to red light in the photomorphogenic responses. The phenotypes of the single and double mutants were also characterized extensively, showing that they exhibited circadian-associated phenotypes characteristic for each. These results are discussed from the viewpoint that PRR9/PRR7/PRR5 together act as period-controlling factors, and they play overlapping and distinctive roles close to (or within) the central oscillator in which the relative, PRR1/TOC1, plays an essential role.

Arabidopsis↗
PubMed2002

Circadian expression of clock genes during ontogeny in the rat heart.

Recent studies have suggested that peripheral tissues in mammals have an autonomous circadian oscillator driven by negative feedback loops consisting of periodical expression of clock genes. In the present study we investigated the mechanism that regulates circadian rhythms in mammalian peripheral tissues, and observed developmental aspects in circadian expression of clock genes in the heart of postnatal rats. Daily expression patterns of clock genes (rPer1, rPer2 and BMAL1) and a clock-controlled gene Dbp were examined by Northern blot analysis. Circadian expression of rPer1, BMAL1 and Dbp mRNAs started between postnatal day 2 (P2) and P5, but rPer2 mRNA did not show rhythmicity until P14. Rhythmic expression of other genes in the heart occurred even in the absence of rhythmic rPer2 expression. These findings suggest that in the rat heart, rhythmic expression of rPer2 was not essential to generate circadian rhythmicity at the early postnatal stage. Judging from mRNA rhythms in the heart, it was probably after P20 that rats established the mature circadian system controlling peripheral rhythms.

ARNTL Transcription Factors↗
PubMed2000

Adaptive significance of a circadian clock: temporal segregation of activities reduces intrinsic competitive inferiority in Drosophila parasitoids.

Most organisms show self-sustained circadian oscillations or biological clocks which control their daily fluctuations in behavioural and physiological activities. While extensive progress has been made in understanding the molecular mechanisms of biological clocks, there have been few clear demonstrations of the fitness value of endogenous rhythms. This study investigated the adaptive significance of circadian rhythms in a Drosophila parasitoid community. The activity rhythms of three sympatric Drosophila parasitoids are out of phase, the competitively inferior parasitoid species being active earlier than the superior competitor. This temporal segregation appears at least partially determined by endogenous periods of the clock which also vary between species and which correlate the time of activity. This earlier activity of the inferior competitor significantly reduces its intrinsic competitive disadvantage when multiparasitism occurs, thus suggesting that natural selection acting on the phase of the rhythm could substantially deviate the endogenous period from the optimal ca. 24 h period. This study demonstrates that temporal segregation of competing species could be endogenously controlled, which undoubtedly favours their coexistence in nature and also shows how natural selection can act on biological clocks to shape daily activity patterns.

Adaptation, Physiological↗
PubMed2006

Coexisting chaotic and periodic dynamics in clock escapements.

This paper addresses the nature of noise in machines. As a concrete example, we examine the dynamics of clock escapements from experimental, historical and analytical points of view. Experiments on two escapement mechanisms from the Reuleaux kinematic collection at Cornell University are used to illustrate chaotic-like noise in clocks. These vibrations coexist with the periodic dynamics of the balance wheel or pendulum. A mathematical model is presented that shows how self-generated chaos in clocks can break the dry friction in the gear train. This model is shown to exhibit a strange attractor in the structural vibration of the clock. The internal feedback between the oscillator and the escapement structure is similar to anti-control of chaos models.

Algorithms↗
PubMed2025

Differential methylation clock ages across buffy coat (BC), peripheral blood mononuclear cells (PBMC), and saliva in individuals approaching midlife.

Understanding epigenetic aging prior to midlife is gaining interest as a potentially intervenable period to address factors that influence health and cognitive aging. Epigenetic changes associated with aging may point to differential biological aging rates; however, methylation profiles may not be substitutable across tissues. We compared DNA methylation in three tissues collected in 91 siblings and twins from the Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife1): saliva, buffy coat (BC), and peripheral blood mononuclear cells (PBMC). Overall, across five methylation clocks and two blood-derived and one saliva-derived tissues, moderate to strong associations between chronological age and methylation ages were observed. Moreover, PBMC methylation age values correlate more strongly with BC values (Spearman r = 0.66 - 0.87), whereas saliva showed weaker correlations with either form of blood-derived measures (Spearman r = 0.25 - 0.69) although still moderate to strong magnitudes. Saliva demonstrated significantly older methylation ages across four of five clocks, whereas PBMC and BC did not differ. Twins were more strongly correlated for BC and PBMC derived clocks with weaker and inconsistent patterns among Saliva clocks. DunedinPACE age acceleration showed no significant tissue differences and on average demonstrated the largest divergence of similarity between monozygotic (MZ) versus dizygotic (DZ) twins (rMZ= .56, rDZ= .21). In summary, saliva-derived methylation is not a direct substitute for blood-derived methylation whereas blood-derived methylation values were comparable across buffy coat and peripheral blood mononuclear cell tissues.

age acceleration↗
PubMed2006

Lcg is a light-inducible and clock-controlled gene expressed in the chicken pineal gland.

The circadian clock is an autonomous biological clock that is entrainable to environmental 24-h cycles by receiving time cues such as light. Generally, light given at early and late subjective night, respectively, delays and advances the phase of the circadian oscillator. We previously searched for the chicken pineal genes that are induced by light in a phase-dependent manner. The present study undertook cDNA cloning and characterization of a gene whose expression was remarkably up-regulated by light at late subjective night. The mRNA level of this gene exhibited robust diurnal change in the pineal gland, with a peak in the early (subjective) day under light-dark cycles and constant dark condition, and hence it was designated Lcg (Light-inducible and Clock-controlled Gene). Chicken Lcg encodes a coiled-coil protein composed of 560 amino acid residues. Among chicken tissues, the pineal gland and the retina exhibited relatively high expression levels of LCG. LCG was colocalized with gamma-tubulin, a centrosomal protein, when expressed in COS7 cells, and LCG is the first example of a clock-related molecule being accumulated at the centrosome. Coimmunoprecipitation of LCG with gamma-tubulin in the chicken pineal lysate suggests a link between the circadian oscillator and the centrosomal function.

Amino Acid Sequence↗
PubMed2007

Clock gene expression in the retina of melatonin-proficient (C3H) and melatonin-deficient (C57BL) mice.

In several mammalian species, the retina contains an autonomous circadian clock and is capable of synthesizing melatonin. The function of circadian clocks depends on interlocking transcriptional/translational feedback loops involving several clock genes. Here we investigated the expression of two clock genes (Per1, Cry2) and the level of phosphorylated (p) cyclic AMP response element binding protein (CREB) in retinae of melatonin-deficient (C57BL) with an intact retina and melatonin-proficient (C3H) mice with degenerated outer nuclear layer. RNase protection assay and in situ hybridization revealed in both strains a rhythm in transcript levels for Per1 with a peak at zeitgeber time (ZT) 08, but not for Cry2. Immunoreactions for PER1, CRY2 and pCREB were localized to the nuclei of cells in the inner nuclear layer (INL) and ganglion cell layer (GC) of both strains and to the outer nuclear layer of C57BL. In C3H, protein levels of PER1 and CRY2 followed a clear day/night rhythm in the INL and the GC with a peak at the end of the day (ZT14). pCREB levels peaked at the beginning of the day. Noteably, in melatonin-deficient C57BL mice, protein levels of PER1, CRY2 and pCREB did not show significant changes over a 16L/8D cycle. These data suggest that melatonin influences PER1 and CRY2 protein levels via post-transcriptional mechanisms and also plays a role in rhythmic regulation of pCREB levels in the mammalian retina.

Animals↗
PubMed2007

Regulation of output from the plant circadian clock.

Plants, like many other organisms, have endogenous biological clocks that enable them to organize their physiological, metabolic and developmental processes so that they occur at optimal times. The best studied of these biological clocks are the circadian systems that regulate daily (approximately 24 h) rhythms. At the core of the circadian system in every organism are oscillators responsible for generating circadian rhythms. These oscillators can be entrained (set) by cues from the environment, such as daily changes in light and temperature. Completing the circadian clock model are the output pathways that provide a link between the oscillator and the various biological processes whose rhythms it controls. Over the past few years there has been a tremendous increase in our understanding of the mechanisms of the oscillator and entrainment pathways in plants and many useful reviews on the subject. In this review we focus on the output pathways by which the oscillator regulates rhythmic plant processes. In the first part of the review we describe the role of the circadian system in regulation at all stages of a plant's development, from germination and growth to reproductive development as well as in multiple cellular processes. Indeed, the importance of a circadian clock for plants can be gauged by the fact that so many facets of plant development are under its control. In the second part of the review we describe what is known about the mechanisms by which the circadian system regulates these output processes.

Arabidopsis↗
PubMed2002

Dopamine mediates circadian clock regulation of rod and cone input to fish retinal horizontal cells.

A circadian (24-hour) clock regulates the light responses of fish cone horizontal cells, second order neurones in the retina that receive synaptic contact from cones and not from rods. Due to the action of the clock, cone horizontal cells are driven by cones in the day, but primarily driven by rods at night. We show here that dopamine, a retinal neurotransmitter, acts as a clock signal for the day by increasing cone input and decreasing rod input to cone horizontal cells. The amount of endogenous dopamine released from in vitro retinae was greater during the subjective day than the subjective night. Application of dopamine or quinpirole, a dopamine D(2)-like agonist, during the subjective night increased cone input and eliminated rod input to the cells, a state usually observed during the subjective day. In contrast, application of spiperone, a D(2)-like antagonist, or forskolin, an activator of adenylyl cyclase, during the subjective day reduced cone input and increased rod input. SCH23390, a D(1) antagonist, had no effect. Application of R(p)-cAMPS, an inhibitor of cAMP-dependent protein kinase, or octanol, an alcohol that uncouples gap junctions, during the night increased cone input and decreased rod input. Because D(2)-like receptors are on photoreceptor cells, but not horizontal cells, the results suggest that the clock-induced increase in dopamine release during the day activates D(2)-like receptors on photoreceptor cells. The resultant decrease in intracellular cyclic AMP and protein kinase A activation then mediates the increase in cone input and decrease in rod input.

Animals↗
PubMed1996

Resetting the Drosophila clock by photic regulation of PER and a PER-TIM complex.

Circadian clocks can be reset by light stimulation. To investigate the mechanism of this phase shifting, the effects of light pulses on the protein and messenger RNA products of the Drosophila clock gene period (per) were measured. Photic stimuli perturbed the timing of the PER protein and messenger RNA cycles in a manner consistent with the direction and magnitude of the phase shift. In addition, the recently identified clock protein TIM (for timeless) interacted with PER in vivo, and this association was rapidly decreased by light. This disruption of the PER-TIM complex in the cytoplasm was accompanied by a delay in PER phosphorylation and nuclear entry and disruption in the nucleus by an advance in PER phosphorylation and disappearance. These results suggest a mechanism for how a unidirectional environmental signal elicits a bidirectional clock response.

Animals↗
PubMed1997

Independent photoreceptive circadian clocks throughout Drosophila.

Transgenic Drosophila that expressed either luciferase or green fluorescent protein driven from the promoter of the clock gene period were used to monitor the circadian clock in explanted head, thorax, and abdominal tissues. The tissues (including sensory bristles in the leg and wing) showed rhythmic bioluminescence, and the rhythms could be reset by light. The photoreceptive properties of the explanted tissues indicate that unidentified photoreceptors are likely to contribute to photic signal transduction to the clock. These results show that autonomous circadian oscillators are present throughout the body, and they suggest that individual cells in Drosophila are capable of supporting their own independent clocks.

Animals↗
PubMed1999

Photic induction of mPer1 and mPer2 in cry-deficient mice lacking a biological clock.

Mice lacking mCry1 and mCry2 are behaviorally arrhythmic. As shown here, cyclic expression of the clock genes mPer1 and mPer2 (mammalian Period genes 1 and 2) in the suprachiasmatic nucleus and peripheral tissues is abolished and mPer1 and mPer2 mRNA levels are constitutively high. These findings indicate that the biological clock is eliminated in the absence of both mCRY1 and mCRY2 (mammalian cryptochromes 1 and 2) and support the idea that mammalian CRY proteins act in the negative limb of the circadian feedback loop. The mCry double-mutant mice retain the ability to have mPer1 and mPer2 expression induced by a brief light stimulus known to phase-shift the biological clock in wild-type animals. Thus, mCRY1 and mCRY2 are dispensable for light-induced phase shifting of the biological clock.

Animals↗
PubMed2004

Splicing of the period gene 3'-terminal intron is regulated by light, circadian clock factors, and phospholipase C.

The daily timing of circadian ( congruent with 24-h) controlled activity in many animals exhibits seasonal adjustments, responding to changes in photoperiod (day length) and temperature. In Drosophila melanogaster, splicing of an intron in the 3' untranslated region of the period (per) mRNA is enhanced at cold temperatures, leading to more rapid daily increases in per transcript levels and earlier "evening" activity. Here we show that daily fluctuations in the splicing of this intron (herein referred to as dmpi8) are regulated by the clock in a manner that depends on the photoperiod (day length) and temperature. Shortening the photoperiod enhances dmpi8 splicing and advances its cycle, whereas the amplitude of the clock-regulated daytime decline in splicing increases as temperatures rise. This suggests that at elevated temperatures the clock has a more pronounced role in maintaining low splicing during the day, a mechanism that likely minimizes the deleterious effects of daytime heat on the flies by favoring nocturnal activity during warm days. Light also has acute inhibitory effects, rapidly decreasing the proportion of dmpi8-spliced per transcript, a response that does not require a functional clock. Our results identify a novel nonphotic role for phospholipase C (no-receptor-potential-A [norpA]) in the temperature regulation of dmpi8 splicing.

3' Untranslated Regions↗
PubMed2005

Anatomical and functional characterization of clock gene expression in neuroendocrine dopaminergic neurons.

Oscillations of gene expression and physiological activity in suprachiasmatic nucleus (SCN) neurons result from autoregulatory feedback loops of circadian clock gene transcription factors. In the present experiment, we have determined the pattern of PERIOD1 (PER1), PERIOD2 (PER2), and CLOCK expression within neuroendocrine dopaminergic (DAergic) neurons (NDNs) of ovariectomized (OVX) rats. We have also determined the effects of per1, per2, and clock mRNA knockdown in the SCN with antisense deoxyoligonucleotides (AS-ODN) on DA release from NDNs. Diurnal rhythms of PER1 and PER2 expression in tuberoinfundibular DAergic (TIDA) and periventricular hypophyseal DAergic (PHDA) neurons, peaked at circadian time (CT)18 and CT12, respectively. Rhythms of PER1 expression in tuberhypophyseal neuroendocrine DAergic (THDA) neurons were undetectable. Rhythms of PER2 expression were found in all three populations of NDNs, with greater levels of PER2 expression between CT6 and CT12. AS-ODN injections differentially affected DA turnover in the axon terminals of the median eminence (ME), neural lobe (NL) and intermediate lobe (IL) of the pituitary gland, resulting in a significant decrease in DA release in the early subjective night in the ME (TIDA), a significant increase in DA release at the beginning of the day in the IL (PHDA), and no effect in the NL (THDA). AS-ODN-treatment induced a rhythm of DA concentration in the anterior lobe, with greater DA levels in the middle of the day. These data suggest that clock gene expression, particularly PER1 and PER2, within NDNs may act to modulate diurnal rhythms of DA release from NDNs in the OVX rat.

ARNTL Transcription Factors↗
PubMed2026

Mathematical modeling of dietary timing- and protein quality-responsive liver circadian clock and its function on ribosome biogenesis.

Independent of the suprachiasmatic nucleus, peripheral clocks can be strongly entrained by dietary signals. Although feeding time has been widely studied, the effects of food quality-particularly nutrient availability and stress-on peripheral circadian entrainment and metabolic regulation remain less understood. We developed a semimechanistic mathematical model of peripheral clock synchronization and clock-controlled ribosome biogenesis (RiBi) in response to feeding/fasting cycles and rhythms in dietary essential amino acid (EAA) availability. The model integrates EAA-sensitive signaling through mammalian target of rapamycin complex 1 (mTORC1) and the general control nonderepressible 2 (GCN2)-mediated integrated stress response (ISR), together with ribosomal protein expression as a metabolic endpoint. We used the model to examine circadian entrainment under nutrient stress, adaptation during transitions between feeding schedules with EAA insufficiency, and stress-related mechanisms that may restore circadian and metabolic function. Simulations showed that mTORC1 and GCN2-ISR signaling jointly regulate metabolic entrainability and stress adaptation and are required to maintain circadian synchronization and RiBi dynamics during nutrient stress. The model also predicted that differences in homeostatic adaptation can produce individualized recovery trajectories after transient dietary disruption. Finally, appropriate modulation of GCN2-ISR signaling mitigated disruption-associated RiBi hyperactivation by leveraging dietary EAA rhythms to restore clock function. These findings identify dietary EAA stress and its regulatory pathways as important determinants of peripheral circadian entrainment and metabolic adaptation, supporting the development of personalized nutrition-based strategies for circadian disruption-related chronic disease.NEW & NOTEWORTHY This study provides a mechanistic modeling framework linking dietary protein quality, EAA-sensitive mTORC1/GCN2-ISR signaling, peripheral circadian entrainment, and ribosome biogenesis, highlighting how nutrient stress may shape individualized circadian recovery and metabolic regulation.

Circadian Clocks↗
PubMed2006

PDF cycling in the dorsal protocerebrum of the Drosophila brain is not necessary for circadian clock function.

In Drosophila, the neuropeptide pigment-dispersing factor (PDF) is a likely circadian molecule, secreted by central pacemaker neurons (LNvs). PDF is expressed in both small and large LNvs (sLNvs and lLNvs), and there are striking circadian oscillations of PDF staining intensity in the small cell termini, which require a functional molecular clock. This cycling may be relevant to the proposed role of PDF as a synchronizer of the clock system or as an output signal connecting pacemaker cells to locomotor activity centers. In this study, the authors use a generic neuropeptide fusion protein (atrial natriuretic factor-green fluorescent protein [ANF-GFP]) and show that it can be expressed in the same neurons as PDF itself. Yet, ANF-GFP as well as PDF itself does not manifest any cyclical accumulation in sLNv termini in adult transgenic flies. Surprisingly, the absence of detectable PDF cycling is not accompanied by any detectable behavioral pheno-type, since these transgenic flies have normal morning and evening anticipation in a light-dark cycle (LD) and are fully rhythmic in constant darkness (DD). The molecular clock is also not compromised. The results suggest that robust PDF cycling in sLNv termini plays no more than a minor role in the Drosophila circadian system and is apparently not even necessary for clock output function.

Animals↗
PubMed2006

Circadian rhythms in murine pups develop in absence of a functional maternal circadian clock.

A genetic approach was used to investigate whether the emergence of circadian rhythms in murine pups is dependent on a functional maternal clock. Arrhythmic females bearing either the mPer1Brdm1/Per2Brdm1 or mPer2Brdm1/Cry1-/- double-mutant genotype were crossed with wild-type males under constant darkness. The heterozygous offspring have the genetic constitution for a functional circadian clock. Individual pups born to arrhythmic mPer1Brdm1/Per2Brdm1 and mPer2Brdm1/Cry1-/- mothers in constant darkness without external zeitgeber developed normal circadian rhythms, but their clocks were less synchronized to each other compared to wild-type animals. These findings indicate that development of circadian rhythms does not depend on a functional circadian clock in maternal tissue, extending previous findings obtained from pups born to SCN-lesioned mothers.

Animals↗