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PubMed2005

Uncovering the design principles of circadian clocks: mathematical analysis of flexibility and evolutionary goals.

In this paper, we present the mathematical details underlying both an approach to the flexibility of regulatory networks and an analytical characterization of evolutionary goals of circadian clock networks. A fundamental problem in cellular regulation is to understand the relation between the form of regulatory networks and their function. Circadian clocks present a particularly interesting instance of this. Recent work has shown that they have complex structures involving multiple interconnected feedback loops with both positive and negative feedback. We address the question of why they have such a complex structure and argue that it is to provide the flexibility necessary to simultaneously attain multiple key properties of circadian clocks such as robust entrainment and temperature compensation. To do this we address two fundamental problems: (A) to understand the relationships between the key evolutionary aims of the clock and (B) to ascertain how flexible the clock's structure is. To address the first problem we use infinitesimal response curves (IRCs), a tool that we believe will be of general utility in the analysis of regulatory networks. To understand the second problem we introduce the flexibility dimension d, show how to calculate it and then use it to analyse a range of models. We believe our results will generalize to a broad range of regulatory networks.

Animals↗
PubMed2003

Timekeeping in bacteria: the cyanobacterial circadian clock.

The prokaryotes known as cyanobacteria possess an endogenous 24h biological (circadian) clock that provides temporal coordination for physiological processes. Although the cyanobacterial clock has the same fundamental properties as circadian clocks in eukaryotes, its components are non-homologous to those of animals, plants or fungi. Moreover, its mechanism is likely to be very different from that depicted in eukaryotic clock models. The picture that is emerging for the timing mechanism in cyanobacteria is of a multiprotein, multimeric, molecular machine composed of proteins whose domains exhibit twists on common themes. Signal transduction into and out of the clock core appears to occur via histidine protein kinase-based phosphorylation relays.

Biological Clocks↗
PubMed2004

Signaling in the mammalian circadian clock: the NO/cGMP pathway.

Mammalian circadian rhythms are generated by a hypothalamic suprachiasmatic nuclei (SCN) clock. Light pulses synchronize body rhythms by inducing phase delays during the early night and phase advances during the late night. Phosphorylation events are known to be involved in circadian phase shifting, both for delays and advances. Pharmacological inhibition of the cGMP-dependent kinase (cGK) or Ca2+/calmodulin-dependent kinase (CaMK), or of neuronal nitric oxide synthase (nNOS) blocks the circadian responses to light in vivo. Light pulses administered during the subjective night, but not during the day, induce rapid phosphorylation of both p-CAMKII and p-nNOS (specifically phosphorylated by CaMKII). CaMKII inhibitors block light-induced nNOS activity and phosphorylation, suggesting a direct pathway between both enzymes. Furthermore, SCN cGMP exhibits diurnal and circadian rhythms with maximal values during the day or subjective day. This variation of cGMP levels appears to be related to temporal changes in phosphodiesterase (PDE) activity and not to guanylyl cyclase (GC) activity. Light pulses increase SCN cGMP levels at circadian time (CT) 18 (when light causes phase advances of rhythms) but not at CT 14 (the time for light-induced phase delays). cGK II is expressed in the hamster SCN and also exhibits circadian changes in its levels, peaking during the day. Light pulses increase cGK activity at CT 18 but not at CT 14. In addition, cGK and GC inhibition by KT-5823 and ODQ significantly attenuated light-induced phase shifts at CT 18. This inhibition did not change c-Fos expression SCN but affected the expression of the clock gene per in the SCN. These results suggest a signal transduction pathway responsible for light-induced phase advances of the circadian clock which could be summarized as follows: Glu-Ca2+-CaMKII-nNOS-GC-cGMP-cGK-->-->clock genes. This pathway offers a signaling window that allows peering into the circadian clock machinery in order to decipher its temporal cogs and wheels.

Animals↗
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↗
PubMed2003

The biological clock: Ca2+ links the pendulum to the hands.

The circadian clock in mammals is located in the hypothalamic suprachiasmatic nucleus. At the core of the clock are molecular autofeedback loops associated with clock gene transcription. However, the mechanisms of circadian signal transduction are basically unknown. A recent report by Ikeda et al. provides new insights into the intracellular signaling pathways involved in conveying circadian clock information from the core loop to cellular functions. Cytosolic Ca(2+) is proposed to be a key substance linking the 'pendulum' to the 'hands' of the clock.

Animals↗
PubMed2005

Orchestrating time: arrangements of the brain circadian clock.

Daily oscillations in physiology and behavior are regulated by a brain clock located in the suprachiasmatic nucleus (SCN). Individual cells within this nucleus contain an autonomous molecular clock. Recent discoveries that make use of new molecular and genetic data and tools highlight the conclusion that the SCN is a heterogeneous network of functionally and phenotypically differentiated cells. Neurons within SCN subregions serve distinctly separate functions in regulating the overall activity of the circadian clock: some cells within the SCN rhythmically express "clock" genes, whereas others exhibit induced expression of these genes after the organism has been exposed to a light pulse. The coordinated interaction of these functionally distinct cells is integral to the coherent functioning of the brain clock.

Animals↗
PubMed2000

Nonphotic phase-shifting in clock mutant mice.

Nonphotic phase-shifting was studied in mice bearing the Clock mutation. First, free-running mice heterozygous for Clock and wild-type mice were induced to become active through a 4-h confinement to a novel running over 3 days. Second, mice exposed to light-dark cycle received daily hypocaloric food during 2 weeks, before being transferred to constant darkness and fed ad libitum. Behavioral activation during the mid-subjective day induced 40-min phase advances in the locomotor activity rhythm of wild-type mice, whereas it produced 50-min phase delays in the circadian behavior of Clock/+ mice. Calorie restriction phase-advanced by 80 min the locomotor activity rhythm in wild-type mice, but not in Clock/+ mice. Therefore, the response of the Clock/+ mice to nonphotic phase shifting differs from that of wild-type mice.

Animals↗
PubMed2005

Analysis of posttranslational regulations in the Neurospora circadian clock.

Posttranslational modification of circadian clock proteins by phosphorylation is an essential regulatory process in the control of eukaryotic circadian clocks. In the Neurospora circadian clock, the key clock protein FREQUENCY (FRQ) is progressively phosphorylated. The phosphorylation of FRQ is regulated by both kinases and phosphatases, and the phosphorylation is important for regulating FRQ stability and its function in the circadian negative feedback loop. The degradation of FRQ is mediated by the ubiquitin/proteasome pathway. This article discusses posttranslational regulations of the Neurospora clock and describes the methods used in the studies of FRQ phosphorylation, FRQ kinases and phosphatases, and FRQ degradation.

Biological Clocks↗
PubMed1997

Functional identification of the mouse circadian Clock gene by transgenic BAC rescue.

As a complementary approach to positional cloning, we used in vivo complementation with bacterial artificial chromosome (BAC) clones expressed in transgenic mice to identify the circadian Clock gene. A 140 kb BAC transgene completely rescued both the long period and the loss-of-rhythm phenotypes in Clock mutant mice. Analysis with overlapping BAC transgenes demonstrates that a large transcription unit spanning approximately 100,000 base pairs is the Clock gene and encodes a novel basic-helix-loop-helix-PAS domain protein. Overexpression of the Clock transgene can shorten period length beyond the wild-type range, which provides additional evidence that Clock is an integral component of the circadian pacemaking system. Taken together, these results provide a proof of principle that "cloning by rescue" is an efficient and definitive method in mice.

Animals↗
PubMed2001

Clock gene expressions in the suprachiasmatic nucleus and other areas of the brain during rhythm splitting in CS mice.

The CS mouse is a mutant strain which displays spontaneous splitting in the circadian locomotor rhythm under continuous darkness. To clarify whether the rhythm splitting occurs in the suprachiasmatic nucleus (SCN) where the mammalian circadian clock is located, the circadian rhythmicities of mammalian clock genes, mPer1, mBMAL1 and mClock, were examined in the SCN and cerebral cortex during rhythm splitting. The circadian profiles of the clock genes during rhythm splitting were essentially the same as those observed under unsplit conditions. However, the mPer1 gene expression throughout the day was bimodal in the piriform and cingulate cortices, peaking in correspondence with two split components of behavioral rhythm. These results indicate that the circadian profiles of three clock gene expressions in the SCN are not consistent with the overt circadian locomotor rhythm, suggesting that the site of rhythm splitting is somewhere outside the SCN, or alternatively different subregions or other clock genes in the SCN are involved in rhythm splitting.

ARNTL Transcription Factors↗
PubMed2001

A novel, associative process modulating photic resetting of the circadian clock.

Appropriate timing of physiological and behavioral processes requires that the circadian clock be reset daily by salient cues in the environment, particularly light. It is known that the ability of light to reset the clock depends both on its intensity and on the circadian time when it is applied (Daan and Pittendrigh, 1976; Moore-Ede et al., 1982). Here we show that the ability of a weak light stimulus to reset the clock is dramatically enhanced when it is presented daily at the same circadian time. Equivalent daily presentations of this light stimulus, but at different circadian times each day, do not lead to such enhancement. These findings suggest that the ability of light to reset the clock can be modified through a novel, and previously unrecognized, conditioning-like associative process in which circadian time serves as the conditioned stimulus and light as the unconditioned stimulus. The idea that circadian time can serve as a conditioned stimulus to modulate the effectiveness of light provides a new perspective on the lasting impact that light schedules have on the circadian clock and, thus, may have implications for existing models of photic entrainment (Pittendrigh and Daan, 1976; Moore-Ede et al., 1982).

Animals↗
PubMed2003

Circadian profile and photic regulation of clock genes in the suprachiasmatic nucleus of a diurnal mammal Arvicanthis ansorgei.

The molecular mechanisms of the mammalian circadian clock located in the suprachiasmatic nucleus have been essentially studied in nocturnal species. Currently, it is not clear if the clockwork and the synchronizing mechanisms are similar between diurnal and nocturnal species. Here we investigated in a day-active rodent Arvicanthis ansorgei, some of the molecular mechanisms that participate in the generation of circadian rhythmicity and processing of photic signals. In situ hybridization was used to characterize circadian profiles of expression of Per1, Per2, Cry2 and Bmal1 in the suprachiasmatic nucleus of A. ansorgei housed in constant dim red light. All the clock genes studied showed a circadian expression. Per1 and Per2 mRNA increased during the subjective day and decreased during the subjective night. Also, Bmal1 exhibited a circadian expression, but in anti-phase to that of Per1. The expression of Cry2 displayed a circadian pattern, increasing during the late subjective day and decreasing during the late subjective night. We also obtained the phase responses to light for wheel-running rhythm and clock gene expression. At a behavioral level, light was able to induce phase shifts only during the subjective night, like in other diurnal and nocturnal species. At a molecular level, light pulse exposure during the night led to an up-regulation of Per1 and Per2 concomitant with a down-regulation of Cry2 in the suprachiasmatic nucleus of A. ansorgei. In contrast, Bmal1 expression was not affected by light pulses at the circadian times investigated. This study demonstrates that light exposure during the subjective night has opposite effects on the expression of the clock genes Per1 and Per2 compared with that of Cry2. These differential effects can participate in photic resetting of the circadian clock. Our data also indicate that the molecular mechanisms underlying circadian rhythmicity and photic synchronization share clear similarities between diurnal and nocturnal mammals.

ARNTL Transcription Factors↗
PubMed2003

Highly conserved Drosophila ananassae timeless gene functions as a clock component in Drosophila melanogaster.

The behavior and physiology of Drosophila are subject to rhythms that are controlled by the circadian clock genes, period, timeless, clock and cycle, all of which are thought to participate in central pacemaker control. The molecular mechanism of rhythm in Drosophila has been studied in detail. However, rhythm and clock genes have mostly been analyzed in Drosophila melanogaster. To confirm whether the tim gene exists and works as a clock component in other Drosophila species, we cloned a tim homolog from Drosophila ananassae that shared 85.9% similarity with Drosophila melanogaster tim at the amino acid level. In addition, the PER interaction domains and NLS were highly conserved. Introduction of the D. ananassae tim homolog rescued the rhythm of the locomotor activity of about 44% of a population of D. melanogaster tim(01) flies. At the molecular level, hs-tim introduced not only TIM but PER oscillation in transgenic flies. These results indicate that the tim gene in D. ananassae functions as a component of the circadian clock in D. melanogaster.

Amino Acid Sequence↗
PubMed2002

Central and peripheral regulation of feeding and nutrition by the mammalian circadian clock: implications for nutrition during manned space flight.

Circadian clocks have evolved to predict and coordinate physiologic processes with the rhythmic environment on Earth. Space studies in non-human primates and humans have suggested that this clock persists in its rhythmicity in space but that its function is altered significantly in long-term space flight. Under normal circumstances, the clock is synchronized by the light-dark cycle via the retinohypothalamic tract and the suprachiasmatic nucleus. It is also entrained by restricted feeding regimes via a suprachiasmatic nucleus-independent circadian oscillator. The site of this suboscillator (or oscillators) is not known, but new evidence has suggested that peripheral tissues in the liver and viscera may express circadian clock function when forced to do so by restricted feeding schedules or other homeostatic disruptions. New research on the role of the circadian clock in the control of feeding on Earth and in space is warranted.

Animals↗
PubMed2001

An Arabidopsis circadian clock component interacts with both CRY1 and phyB.

Most organisms, from cyanobacteria to mammals, use circadian clocks to coordinate their activities with the natural 24-h light/dark cycle. The clock proteins of Drosophila and mammals exhibit striking homology but do not show similarity with clock proteins found so far from either cyanobacteria or Neurospora. Each of these organisms uses a transcriptionally regulated negative feedback loop in which the messenger RNA levels of the clock components cycle over a 24-h period. Proteins containing PAS domains are invariably found in at least one component of the characterized eukaryotic clocks. Here we describe ADAGIO1 (ADO1), a gene of Arabidopsis thaliana that encodes a protein containing a PAS domain. We found that a loss-of-function ado1 mutant is altered in both gene expression and cotyledon movement in circadian rhythmicity. Under constant white or blue light, the ado1 mutant exhibits a longer period than that of wild-type Arabidopsis seedlings, whereas under red light cotyledon movement and stem elongation are arrhythmic. Both yeast two-hybrid and in vitro binding studies show that there is a physical interaction between ADO1 and the photoreceptors CRY1 and phyB. We propose that ADO1 is an important component of the Arabidopsis circadian system.

Animals↗
PubMed1998

Zebrafish Clock rhythmic expression reveals independent peripheral circadian oscillators.

The only vertebrate clock gene identified by mutagenesis is mouse Clock, which encodes a bHLH-PAS transcription factor. We have cloned Clock in zebrafish and show that, in contrast to its mouse homologue, it is expressed with a pronounced circadian rhythm in the brain and in two defined pacemaker structures, the eye and the pineal gland. Clock oscillation was also found in other tissues, including kidney and heart. In these tissues, expression of Clock continues to oscillate in vitro. This demonstrates that self-sustaining circadian oscillators exist in several vertebrate organs, as was previously reported for invertebrates.

Amino Acid Sequence↗
PubMed1998

Clock controls circadian period in isolated suprachiasmatic nucleus neurons.

The suprachiasmatic nucleus (SCN) is the master circadian pacemaker in mammals, and one molecular regulator of circadian rhythms is the Clock gene. Here we studied the discharge patterns of SCN neurons isolated from Clock mutant mice. Long-term, multielectrode recordings showed that heterozygous Clock mutant neurons have lengthened periods and that homozygous Clock neurons are arrhythmic, paralleling the effects on locomotor activity in the animal. In addition, cells in dispersals expressed a wider range of periods and phase relationships than cells in explants. These results suggest that the Clock gene is required for circadian rhythmicity in individual SCN cells and that a mechanism within the SCN synchronizes neurons and restricts the range of expressed circadian periods.

Animals↗
PubMed2005

Constant light desynchronizes mammalian clock neurons.

Circadian organization can be disrupted by constant light, resulting in behavioral arrhythmicity or 'splitting' of rhythms of activity and rest. By imaging molecular rhythms of individual clock neurons in explanted mouse clock nuclei, we now find that constant light desynchronizes clock neurons but does not compromise their ability to generate circadian rhythms. Cellular synchrony within clock nuclei is disrupted during arrhythmicity, whereas neurons in the left and right clock nuclei cycle in antiphase during 'splitting.'

Animals↗