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PubMed2004

Effects of age on circadian rhythms are similar in wild-type and heterozygous Clock mutant mice.

The amplitudes of many circadian rhythms, at the behavioral, physiological, cellular, and biochemical levels, decrease with advanced age. Previous studies suggest that the amplitude of the central circadian pacemaker is decreased in old animals. Recently, it has been reported that expression of several circadian clock genes, including Clock, is lower in the master circadian pacemaker of old rodents. To test the hypothesis that decreased activity of a circadian clock gene renders animals more susceptible to the effects of aging, we analyzed the circadian rhythm of locomotor activity in young and old wild-type and heterozygous Clock mutant mice. We found that the effects of age and the Clock mutation were additive. These results indicate that age-related changes in circadian rhythmicity occur equally in wild-type and heterozygous Clock mutants, suggesting that the Clock mutation does not render mice more susceptible to the effects of age on the circadian pacemaker.

Aging↗
PubMed2006

Genomic organization of the rat Clock gene and sequence analysis in inbred rat strains.

While mutations in genes that function in the core molecular clock may disrupt circadian periodicity, their relevance to diurnal variation in metabolic, cardiovascular, and respiratory function is unknown. The circadian Clock gene product is an essential regulator of central and peripheral circadian rhythms in mammals. We have elucidated the complete exon-intron organization of the Clock gene in rat and have carried out an extensive search for single nucleotide polymorphisms (SNPs) in a panel of 12 inbred rat strains that exhibit diversity in studies of central and peripheral organ function and disease. The rat Clock gene consists of 23 exons spanning approximately 75 kb. Comparative sequence analysis identified 33 novel SNPs, including 32 that distinguish the Brown Norway (BN) rat from the other strains studied. Most notable were two novel mutations in the BN sequence at exon 8, Ile131Val and Ile132Val, occurring in a segment of the highly conserved PAS-A domain of the protein. These results afford the opportunity to assess the impact of genetic variation in Clock on central and peripheral functions subject to the core molecular clock and to test the importance of Clock variants in explaining diversity among rat strains in the expression of phenotypes, such as blood pressure, subject to circadian oscillation.

5' Untranslated Regions↗
PubMed2000

The Xenopus clock gene is constitutively expressed in retinal photoreceptors.

Many aspects of normal retinal physiology are controlled by a retinal circadian clock. In Xenopus laevis, the photoreceptor cells within the retina contain a circadian clock that controls melatonin release. In this report we present the cloning and characterization of the Xenopus homolog of the Clock gene, known to be critical for normal circadian behavioral rhythms in the mouse. The Xenopus Clock gene is expressed primarily in photoreceptors within the eye and is expressed at constant levels throughout the day. Analysis of other tissues revealed that, as in other species, the Xenopus Clock gene is widely expressed. This characterization of the Clock gene provides a useful tool for further exploration of the role of the circadian clock in normal retinal function.

Amino Acid Sequence↗
PubMed1999

Cellular circadian clocks in the pineal.

Daily rhythms are a fundamental feature of all living organisms; most are synchronized by the 24 hr light/dark (LD) cycle. In most species, these rhythms are generated by a circadian system, and free run under constant conditions with a period close to 24 hr. To function properly the system needs a pacemaker or clock, an entrainment pathway to the clock, and one or more output signals. In vertebrates, the pineal hormone melatonin is one of these signals which functions as an internal time-keeping molecule. Its production is high at night and low during day. Evidence indicates that each melatonin producing cell of the pineal constitutes a circadian system per se in non-mammalian vertebrates. In addition to the melatonin generating system, they contain the clock as well as the photoreceptive unit. This is despite the fact that these cells have been profoundly modified from fish to birds. Modifications include a regression of the photoreceptive capacities, and of the ability to transmit a nervous message to the brain. The ultimate stage of this evolutionary process leads to the definitive loss of both the direct photosensitivity and the clock, as observed in the pineal of mammals. This review focuses on the functional properties of the cellular circadian clocks of non-mammalian vertebrates. How functions the clock? How is the photoreceptive unit linked to it and how is the clock linked to its output signal? These questions are addressed in light of past and recent data obtained in vertebrates, as well as invertebrates and unicellulars.

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↗
PubMed1978

Evidence for existence of a yearly clock in surgically and self-blinded chipmunks.

By use of simplified technique and constant environmental conditions, I have demonstrated the existence in the chipmunk of a yearly clock. In a blinded chipmunk the clock manifested itself by remarkably consistent changes in running activity, food and water intake, and body weight over 6 1/2 yr. Studies on freshly trapped chipmunks kept in the same laboratory environment but with alternating light and darkness (12 hr each), showed that, when their eyes were covered for much of the light period, they reduced their exposure to light to preserve the activity of the yearly clock. Laboratory-adapted chipmunks that do not shield their eyes from light do not show the clock. The yearly clock has all the characteristics of the 24-hr clock, including sharply defined active and inactive phases, and must likewise play an important part in the animal's survival. Light would appear to be the chief or only cue for the clock. The period lengths did not change with age during the 6 1/2 yr.

Animals↗
PubMed2005

Importin alpha/beta mediates nuclear transport of a mammalian circadian clock component, mCRY2, together with mPER2, through a bipartite nuclear localization signal.

Circadian rhythms, which period is approximately one day, are generated by endogenous biological clocks. These clocks are found throughout the animal kingdom, as well as in plants and even in prokaryotes. Molecular mechanisms for circadian rhythms are based on transcriptional oscillation of clock component genes, consisting of interwoven autoregulatory feedback loops. Among the loops, the nuclear transport of clock proteins is a crucial step for transcriptional regulation. In the present study, we showed that the nuclear entry of mCRY2, a mammalian clock component, is mediated by the importin alpha/beta system through a bipartite nuclear localization signal in its carboxyl end. In vitro transport assay using digitonin-permeabilized cells demonstrated that all three importin alphas, alpha1 (Rch1), alpha3 (Qip-1), and alpha7 (NPI-2), can mediate mCRY2 import. mCRY2 with the mutant nuclear localization signal failed to transport mPER2 into the nucleus of mammalian cultured cells, indicating that the nuclear localization signal identified in mCRY2 is physiologically significant. These results suggest that the importin alpha/beta system is involved in nuclear entry of mammalian clock components, which is indispensable to transcriptional oscillation of clock genes.

Active Transport, Cell Nucleus↗
PubMed2006

Molecular analysis of clock gene expression in the avian brain.

Birds are equipped with a complex circadian pacemaking system that regulates the rhythmicity of physiology and behavior. As with all organisms, transcriptional and translational feedback loops of clock genes represent the basic molecular mechanism of rhythm generation in birds. To investigate avian clock gene expression, partial cDNA sequences of six mammalian clock gene homologs (Bmal1, Clock, Per2, Per3, Cry1, and Cry2) and a novel avian cryptochrome gene (Cry4) were cloned from the house sparrow, a model system in circadian research. Expression patterns were analyzed by semi-quantitative RT-PCR and RNase protection assays using total RNA extracted from adult male house sparrow brains. With the exception of Cry4, pronounced rhythmic mRNA expression of all the clock genes analyzed was encountered, with mRNA levels varying considerably between the various genes. Although some basic features of the molecular circadian feedback loop appear to be similar between mammals and birds, the precise phase relationships of the clock gene mRNA rhythms relative to each other and to the light zeitgeber differ significantly between the house sparrow and mammals. Our results point to the existence of differences in the organization of avian and mammalian circadian clock mechanisms.

ARNTL Transcription Factors↗
PubMed2006

High-fat feeding exerts minimal effects on rhythmic mRNA expression of clock genes in mouse peripheral tissues.

Recent studies have suggested that the impairment of the circadian molecular clock in peripheral tissues, including adipose tissue, is involved in the development of metabolic syndrome. Although the disorder is often caused by dietary obesity, it remains to be elucidated whether dietary obesity or high-caloric intake per se affects the molecular clock system. To address this issue, this study investigated the effect of high-fat feeding on the rhythmic mRNA expression of clock genes (Clock, Bmal1, Per1, Per2, Cry1, Cry2, and Dbp) in mouse visceral adipose tissue and liver. Mice fed a high-fat diet for 8 wks developed a mild but overt metabolic syndrome of obesity, hyperlipidemia, and hyperglycemia. However, the high-fat feeding had only minimal effects on the rhythmic expression of the clock genes examined in both tissues. On the other hand, daily rhythmicity in the transcript level of cholesterol 7alpha-hydroxylase, a hepatic enzyme controlling circadian cholesterol homeostasis, disappeared in the mice on high-fat chow. These results suggest that high-fat feeding and mild metabolic syndrome scarcely alter the molecular clock system in mouse peripheral tissues, and that physiological circadian rhythms could be affected without altering the system. Further studies are needed to better understand the role of the circadian molecular clock in the development of metabolic syndrome. The first two authors contributed equally to this study.

Animal Feed↗
PubMed2001

Altered behavioral rhythms and clock gene expression in mice with a targeted mutation in the Period1 gene.

A group of specialized genes has been defined to govern the molecular mechanisms controlling the circadian clock in mammals. Their expression and the interactions among their products dictate circadian rhythmicity. Three genes homologous to Drosophila period exist in the mouse and are thought to be major players in the biological clock. Here we present the generation of mice in which the founding member of the family, Per1, has been inactivated by homologous recombination. These mice present rhythmicity in locomotor activity, but with a period almost 1 h shorter than wild-type littermates. Moreover, the expression of clock genes in peripheral tissues appears to be delayed in Per1 mutant animals. Importantly, light-induced phase shifting appears conserved. The oscillatory expression of clock genes and the induction of immediate-early genes in response to light in the master clock structure, the suprachiasmatic nucleus, are unaffected. Altogether, these data demonstrate that Per1 plays a distinct role within the Per family, as it may be involved predominantly in peripheral clocks and/or in the output pathways of the circadian clock.

Animals↗
PubMed2003

The frequency gene is required for temperature-dependent regulation of many clock-controlled genes in Neurospora crassa.

The circadian clock of Neurospora broadly regulates gene expression and is synchronized with the environment through molecular responses to changes in ambient light and temperature. It is generally understood that light entrainment of the clock depends on a functional circadian oscillator comprising the products of the wc-1 and wc-2 genes as well as those of the frq gene (the FRQ/WCC oscillator). However, various models have been advanced to explain temperature regulation. In nature, light and temperature cues reinforce one another such that transitions from dark to light and/or cold to warm set the clock to subjective morning. In some models, the FRQ/WCC circadian oscillator is seen as essential for temperature-entrained clock-controlled output; alternatively, this oscillator is seen exclusively as part of the light pathway mediating entrainment of a cryptic "driving oscillator" that mediates all temperature-entrained rhythmicity, in addition to providing the impetus for circadian oscillations in general. To identify novel clock-controlled genes and to examine these models, we have analyzed gene expression on a broad scale using cDNA microarrays. Between 2.7 and 5.9% of genes were rhythmically expressed with peak expression in the subjective morning. A total of 1.4-1.8% of genes responded consistently to temperature entrainment; all are clock controlled and all required the frq gene for this clock-regulated expression even under temperature-entrainment conditions. These data are consistent with a role for frq in the control of temperature-regulated gene expression in N. crassa and suggest that the circadian feedback loop may also serve as a sensor for small changes in ambient temperature.

Biological Clocks↗
PubMed1980

The frq locus in Neurospora crassa: a key element in circadian clock organization.

Four new circadian clock mutants of Neurospora crassa have been isolated that alter the period length of the circadian conidiation rhythm. Three of these are at the frq locus on linkage group VIIR, where four other clock mutants are located. In contrast to wild type, which has a period length of 21.6 hr, frq-6 has a period length of 19 hr, while frq-7 and frq-8 have period lengths of 29 hr and represent the largest effects of any single gene mutants on circadian periodicity. Thus, seven mutants have now been isolated that map to the frq locus, with period lengths ranging from 16.5 to 29 hr, and each mutant alters clock periodicity by an integral multiple of 2.5 hr. In addition, all frq mutants show incomplete dominance in heterokaryons. The large percentage of clock mutants that map to this locus, coupled with their unique properties, suggests that the frq locus plays an important role in clock organization.--The fourth mutant, designated chrono (chr), has a period length of 23.5 hr, shows incomplete dominance and is unlinked to either of the previously identified clock loci, frq or prd (formerly called frq-5). Double mutants between various combinations of clock mutants show additive effects and indicate no significant gene interaction among mutants at these three loci.

Biological Clocks↗
PubMed1998

Circadian regulation of a Drosophila homolog of the mammalian Clock gene: PER and TIM function as positive regulators.

The Clock gene plays an essential role in the manifestation of circadian rhythms (approximately 24 h) in mice and is a member of the basic helix-loop-helix (bHLH) PER-ARNT-SIM (PAS) superfamily of transcription factors. Here we report the characterization of a novel Drosophila bHLH-PAS protein that is highly homologous to mammalian CLOCK. (Similar findings were recently described by Allada et al. Cell 93:791-804, 1998, and Darlington et al., Science 280:1599-1603, 1998.) Transcripts from this putative Clock ortholog (designated dClock) undergo daily rhythms in abundance that are antiphase to the cycling observed for the RNA products from the Drosophila melanogaster circadian clock genes period (per) and timeless (tim). Furthermore, dClock RNA cycling is abolished and the levels are at trough values in the absence of either PER or TIM, suggesting that these two proteins can function as transcriptional activators, a possibility which is in stark contrast to their previously characterized role in transcriptional autoinhibition. Finally, the temporal regulation of dClock expression is quickly perturbed by shifts in light-dark cycles, indicating that this molecular rhythm is closely connected to the photic entrainment pathway. The isolation of a Drosophila homolog of Clock together with the recent discovery of mammalian homologs of per indicate that there is high structural conservation in the integral components underlying circadian oscillators in Drosophila and mammals. Nevertheless, because mammalian Clock mRNA is constitutively expressed, our findings are a further example of striking differences in the regulation of putative circadian clock orthologs in different species.

Amino Acid Sequence↗
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↗
PubMed2003

Noncircadian regulation and function of clock genes period and timeless in oogenesis of Drosophila melanogaster.

Circadian clock genes are ubiquitously expressed in the nervous system and peripheral tissues of complex animals. While clock genes in the brain are essential for behavioral rhythms, the physiological roles of these genes in the periphery are not well understood. Constitutive expression of the clock gene period was reported in the ovaries of Drosophila melanogaster; however, its molecular interactions and functional significance remained unknown. This study demonstrates that period (per) and timeless (tim) are involved in a novel noncircadian function in the ovary. PER and TIM are constantly expressed in the follicle cells enveloping young oocytes. Genetic evidence suggests that PER and TIM interact in these cells, yet they do not translocate to the nucleus. The levels of TIM and PER in the ovary are affected neither by light nor by the lack of clock-positive elements Clock (Clk) and cycle (cyc). Taken together, these data suggest that per and tim are regulated differently in follicle cells than in clock cells. Experimental evidence suggests that a novel fitness-related phenotype may be linked to noncircadian expression of clock genes in the ovaries. Mated females lacking either per or tim show nearly a 50% decline in progeny, and virgin females show a similar decline in the production of mature oocytes. Disruption of circadian mechanism by either the depletion of TIM via constant light treatment or continuous expression of PER via GAL4/UAS expression system has no adverse effect on the production of mature oocytes.

Animals↗
PubMed2004

Dec1 and Dec2 expression is disrupted in the suprachiasmatic nuclei of Clock mutant mice.

DEC1 and DEC2 are basic helix-loop-helix transcription factors that functionally resemble negative feedback components of the mammalian circadian clock. The genes Dec1 and Dec2 are expressed rhythmically in the rat suprachiasmatic nuclei, and Dec1 expression is stimulated by light in a time-dependent manner with the kinetics of an immediate early gene. DEC1 and DEC2 can inhibit CLOCK:BMAL1 transactivation of the clock gene Per1, suggesting that these transcription factors may help regulate circadian timing. The authors present data on the expression pattern of Dec1 and Dec2 in wild-type and homozygous Clock mutant mice. In the suprachiasmatic nuclei, the Clock mutation significantly reduces the expression of Dec1 and Dec2. Dec1 becomes arrhythmic; Dec2 remains weakly rhythmic in a 12L:12D light-dark cycle but is arrhythmic in constant darkness. A robust attenuation of the Dec1 and Dec2 signals in Clock mutant mice was detected in all brain areas examined. These data point to up-regulation of Dec1 and Dec2 by Clock in vivo.

Animals↗
PubMed2006

Clock-gated photic stimulation of timeless expression at cold temperatures and seasonal adaptation in Drosophila.

Numerous lines of evidence indicate that the initial photoresponse of the circadian clock in Drosophila melanogaster is the light-induced degradation of TIMELESS (TIM). This posttranslational mechanism is in sharp contrast to the well-characterized pacemakers in mammals and Neurospora, where light evokes rapid changes in the transcriptional profiles of 1 or more clock genes. The authors show that light has novel effects on D. melanogaster circadian pacemakers, acutely stimulating the expression of tim at cold but not warm temperatures. This photoinduction occurs in flies defective for the classic visual phototransduction pathway or the circadian-relevant photoreceptor CRYPTOCHROME (CRY). Cold-specific stimulation of tim RNA abundance is regulated at the transcriptional level, and although numerous lines of evidence indicate that period (per) and tim expression are activated by the same mechanism, light has no measurable acute effect on per mRNA abundance. Moreover, light-induced increases in the levels of tim RNA are abolished or greatly reduced in the absence of functional CLOCK (CLK) or CYCLE (CYC) but not PER or TIM. These findings add to a growing number of examples where molecular and behavioral photoresponses in Drosophila are differentially influenced by "positive" (e.g., CLK and CYC) and "negative" (e.g., PER and TIM) core clock elements. The acute effects of light on tim expression are temporally gated, essentially restricted to the daily rising phase in tim mRNA levels. Because the start of the daily upswing in tim expression begins several hours after dawn in long photoperiods (day length), this gating mechanism likely ensures that sunrise does not prematurely stimulate tim expression during unseasonally cold spring/summer days. The results suggest that the photic stimulation of tim expression at low temperatures is part of a seasonal adaptive response that helps advance the phase of the clock on cold days, enabling flies to exhibit preferential daytime activity despite the (usually) earlier onset of dusk. Taken together with prior findings, the ability of temperature and photoperiod to adjust trajectories in the rising phases of 1 or more clock RNAs constitutes a major mechanism contributing to seasonal adaptation of clock function.

Adaptation, Physiological↗
PubMed2007

Hofbauer-Buchner eyelet affects circadian photosensitivity and coordinates TIM and PER expression in Drosophila clock neurons.

Extraretinal photoreception is a common input route for light resetting signals into the circadian clock of animals. In Drosophila melanogaster, substantial circadian light inputs are mediated via the blue light photoreceptor CRYPTOCHROME (CRY) expressed in clock neurons within the brain. The current model predicts that, upon light activation, CRY interacts with the clock proteins TIMELESS (TIM) and PERIOD (PER), thereby inducing their degradation, which in turn leads to a resetting of the molecular oscillations within the circadian clock. Here the authors investigate the function of another putative extraretinal circadian photoreceptor, the Hofbauer-Buchner eyelet (H-B eyelet), located between the retina and the medulla in the fly optic lobes. Blocking synaptic transmission between the H-B eyelet and its potential target cells, the ventral circadian pacemaker neurons, impaired the flies' ability to resynchronize their behavior under jet-lag conditions in the context of nonfunctional retinal photoreception and a mutation in the CRY-encoding gene. The same manipulation also affected synchronized expression of the clock proteins TIM and PER in different subsets of the clock neurons. This shows that synaptic communication between the H-B eyelet and clock neurons contributes to synchronization of molecular and behavioral rhythms and confirms that the H-B eyelet functions as a circadian photoreceptor. Blockage of synaptic transmission from the H-B eyelet in the presence of functional compound eyes and the absence of CRY also results in increased numbers of flies that are unable to synchronize to extreme photoperiods, supplying independent proof for the role of the H-B eyelet as a circadian photoreceptor.

Animals↗