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PubMed2006

Immunoreactivities to three circadian clock proteins in two ground crickets suggest interspecific diversity of the circadian clock structure.

The closely related crickets Dianemobius nigrofasciatus and Allonemobius allardi exhibit similar circadian rhythms and photoperiodic responses, suggesting that they possess similar circadian and seasonal clocks. To verify this assumption, antisera to Period (PER), Doubletime (DBT), and Cryptochrome (CRY) were used to visualize circadian clock neurons in the cephalic ganglia. Immunoreactivities referred to as PER-ir, DBT-ir, and CRY-ir were distributed mainly in the optic lobes (OL), pars intercerebralis (PI), dorsolateral protocerebrum, and the subesophageal ganglion (SOG). A system of immunoreactive cells in the OL dominates in D. nigrofasciatus, while immunoreactivities in the PI and SOG prevail in A. allardi. Each OL of D. nigrofasciatus contains 3 groups of cells that coexpress PER-ir and DBT-ir and send processes over the frontal medulla face to the inner lamina surface, suggesting functional linkage to the compound eye. Only 2 pairs of PER-ir cells (no DBT-ir) were found in the OL of A. allardi. Several groups of PER-ir cells occur in the brain of both species. The PI also contains DBT-ir and CRY-ir cells, but in A. allardi, most of the DBT-ir is confined to the SOG. Most immunoreactive cells in the PI and in the dorsolateral brain send their fibers to the contralateral corpora cardiaca and corpora allata. The proximity and, in some cases, proven identity of the PER-ir, DBT-ir, and CRY-ir perikarya are consistent with presumed interactions between the examined clock components. The antigens were always found in the cytoplasm, and no diurnal oscillations in their amounts were detected. The photoperiod, which controls embryonic diapause, the rate of larval development, and the wing length of crickets, had no discernible effect on either distribution or the intensity of the immunostaining.

Animals↗

PubMed1997

Regulation of cAMP response element binding protein (CREB) binding in the mammalian clock pacemaker by light but not a circadian clock.

Mammalian circadian rhythms are considered to be regulated by a clock pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. The molecular mechanism of entrainment and oscillation of circadian rhythm are not well understood but photic induction of immediate-early gene (IEG) expression in the SCN is thought to play a role. Here we show that under 12 h light:12 h dark (LD) condition, the cAMP response element binding protein (CREB) binding to cAMP responsive promoter element (CRE) of NMDAR1/zeta1 promoter region in the SCN is higher during the light than the dark by electro-mobility shift assay (EMSA). When animals are placed in constant dark, CREB DNA binding activity in the SCN is low and does not vary with circadian time when compared with cortex nuclear extract as a control. Most significantly, photic induction of CREB binding activity in the SCN occurs at all circadian times tested, indicating that CREB DNA binding in the SCN is not gated by the endogenous clock. These results implicate the role of CREB in photic neuronal signaling in the SCN and suggest that CREB DNA binding activities may not be regulated by a circadian clock.

Animals↗

PubMed2004

Temporal and spatial expression patterns of canonical clock genes and clock-controlled genes in the suprachiasmatic nucleus.

In mammals, the suprachiasmatic nuclei (SCN) of the hypothalamus control endogenous circadian rhythms and entrainment to the environment. A core SCN region of calbindin (CalB)-containing cells is retinorecipient and the cells therein lack rhythmic expression of clock genes and electrical activity. The core is surrounded by a 'shell' of rhythmic oscillator cells. In the present experiments, we studied the spatial arrangement of oscillator cells by examining the spatial and temporal patterns of expression of the canonical clock genes Per1, Per2 and vasopressin mRNA, a clock-controlled gene. Surprisingly, in the SCN shell, the dorsomedial cells were the first to rhythmically express both Per1 and VP mRNA, with gene expression then spreading very slowly through much of the nucleus for the next 12 h then receding to baseline levels. Following a light pulse, Per expression increased after 1 h in the core SCN and after 1.5 h in the shell. Although expression in the shell occurred earlier in light-pulsed animals than in those housed in constant darkness, it still followed the same spatial and temporal expression pattern as was observed in constant darkness. The results suggest that not only is the SCN organized into light-responsive and rhythmic regions but also that the rhythmic region of the SCN itself has an ordered arrangement of SCN oscillator cells.

Animals↗

PubMed2001

A mouse genetic locus with death clock and life clock features.

A senility syndrome, with weight loss and priapism, occurs in CBAT6/T6 mice, an exceptionally long-lived strain. Instead of dying at the expected time, these mice get senile weight loss and priapism and go on living. We have postulated that a mutant death clock kills the wrong neurons. Crosses with the NZW and C57BL/6 strains show causation by a single genetic locus (Priap1), with a pronounced gene dosage effect on timing. We report here that various cancers were the cause of death in 31 of 32 NZW mice, compared to only five of 22 CBAT6/T6 mice, a highly significant difference (P<0.001). The longevity of (CBAT6/T6xNZW)F1 hybrids, and the segregation of longevity with priapism and senile weight loss in (CBAT6/T6xNZW) F2 hybrids, indicates that Priap1, or a linked gene, inhibits the cancers that usually shorten the lives of NZW mice. If a timer gene is involved, the cancer resistance action could be because the locus impedes the normal mid-life regression of anti-cancer defence. The priapism suggests loss of the medullary reticular formation neurons which normally inhibit male spinal sexual reflexes. In this region of the medulla there are also the respiratory and cardiac control centres, where apoptotic neuron destruction by the wild-type locus could govern maximal life-span. The CBAT6/T6 locus may be a mutant life-stage control clock. Its discovery could be the revelation of a new, major class of aetiology of disease.

Aging↗

PubMed2002

Structure and function from the circadian clock protein KaiA of Synechococcus elongatus: a potential clock input mechanism.

In the cyanobacterium Synechococcus elongatus (PCC 7942) the proteins KaiA, KaiB, and KaiC are required for circadian clock function. We deduced a circadian clock function for KaiA from a combination of biochemical and structural data. Both KaiA and its isolated carboxyl-terminal domain (KaiA180C) stimulated KaiC autophosphorylation and facilitated attenuation of KaiC autophosphorylation by KaiB. An amino-terminal domain (KaiA135N) had no function in the autophosphorylation assay. NMR structure determination showed that KaiA135N is a pseudo-receiver domain. We propose that this pseudo-receiver is a timing input-device that regulates KaiA stimulation of KaiC autophosphorylation, which in turn is essential for circadian timekeeping.

Bacterial Proteins↗

PubMed1994

Negative feedback defining a circadian clock: autoregulation of the clock gene frequency.

The frequency (frq) locus of Neurospora crassa was originally identified in searches for loci encoding components of the circadian clock. The frq gene is now shown to encode a central component in a molecular feedback loop in which the product of frq negatively regulated its own transcript, which resulted in a daily oscillation in the amount of frq transcript. Rhythmic messenger RNA expression was essential for overt rhythmicity in the organism and no amount of constitutive expression rescued normal rhythmicity in frq loss-of-function mutants. Step reductions in the amount of FRQ-encoding transcript set the clock to a specific and predicted phase. These results establish frq as encoding a central component in a circadian oscillator.

Base Sequence↗

PubMed1998

Circadian rhythm and light responsiveness of BMAL1 expression, a partner of mammalian clock gene Clock, in the suprachiasmatic nucleus of rats.

To clarify whether BMAL1 is involved in the photic signal transduction in the mammalian circadian clock, we examined the effects of a single light pulse on the level of BMAL1 mRNA in the suprachiasmatic nucleus (SCN) of rats by in situ hybridization. Rats were exposed to 30 min light of ca. 300 lux at six different phases in constant darkness and decapitated 60 min later. BMAL1 transcripts in the SCN of the control animals showed a robust circadian oscillation with the highest expression at ZT (Zeitgeber time) 18 and the lowest at ZT2. The light pulse slightly increased the level of BMAL1 transcripts in the SCN. However, the increment did not depend on the phase of light pulse. There was no significant change in the BMAL1 mRNA level up to 120 min after a light pulse at ZT14 and ZT22. These results indicate that BMAL1 transcription is not involved in the photic signal transduction responsible for non-parametric entrainment of the circadian clock in rats.

ARNTL Transcription Factors↗

PubMed2006

Validity of clock drawing test (CDT), scoring by Chula clock-drawing scoring system (CCSS) in screening dementia among Thai elderly in community.

OBJECTIVE: The present paper was to study the validity of screening dementia among Thai elderly by clock drawing test (CDT). MATERIAL AND METHOD: The scoring method selected to apply with CDT was Chula clock-drawing scoring system (CCSS) that was originally developed as clinically-based in Thai elderly patients. The 669 elderly subjects gathered from "Rom Klao" community in Bangkok, Thailand were asked to perform CDT and be examined by a neurologist, using NINCDS-ADRDA diagnosis criteria for probable Alzheimer's disease (AD). CDT was scored by psychiatrists using CCSS. RESULTS: The authors found the demented by clinical diagnosis in 25 cases. Using a CCSS cutoff score of 7, CDT produced positive test results in 191 subjects. Sensitivity was 88%, the specificity was 74% and the area under receiver operation characteristics (ROC) curve was 0.91. The results also showed that comparatively to cutoff point 7, a cutoff point 6 would contribute the higher specificity of 82% and have a similar sensitivity of 88% in this community-based sample. CONCLUSION: The present study provided strong support that CDT scoring by CCSS is efficient to screen dementia in the general community with satisfactory sensitivity and specificity. However modifying the CCSS cutoff score from 7 to 6 increases the specificity and is proposed to be applied in the community.

Aged↗

PubMed1994

On the molecular mechanism of the circadian clock. The 41,000 M(r) clock protein of Chlorella was identified as 3-phosphoglycerate kinase.

A 41,000 M(r) polypeptide of Chlorella exhibits a circadian rhythm in its synthesis and possesses characteristic features of a putative essential clock protein as was proposed by the coupled translation-membrane model. Purification of this polypeptide and a microsequencing analysis yielded a N-terminal sequence of 35 amino acids that showed no homology to known sequences that were thought to be involved in circadian rhythm such as the per gene of Drosophila and the frq gene of Neurospora. However, strong homology was observed to 3-phosphoglycerate kinase (PGK) of different organisms. The highest homology (83%) of this Chlorella sequence was found with the PGK of wheat chloroplast. PGK activity and the 41,000 M(r) polypeptide co-purified through differential centrifugation and gel filtration. These data, and comparison with the physical properties of other known PGK molecules, support the conclusion that the 41,000 M(r) polypeptide of Chlorella, a candidate for a putative essential clock protein, is 3-phosphoglycerate kinase.

Amino Acid Sequence↗

PubMed1981

On the 'clock' mechanism determining the time of tissue-specific enzyme development during ascidian embryogenesis. II. Evidence for association of the clock with the cycle of DNA replication.

Acetylcholinesterase (AChE) is a tissue-specific enzyme of the muscle cells of ascidian embryos and its synthesis begins at the neurula stage. Embryos which had been permanently cleavage-arrested with cytochalasin B could develop AChE activity. The time of first AChE occurrence in embryos which had been arrested in the 32-cell stage with cytochalasin was about the same as in normal embryos. The nucleus in the cell of cytochalasin-arrested embryos divided in good synchrony with that of normal embryos. Embryos which had been continuously arrested with colchicine could also produce AChE activity at nearly the same time as did normal embryos. In the cell of colchicine-arrested embryos normal nuclear divisions did not occur, but the cell showed repeated cycles of nuclear envelope breakdown and nuclear envelope reformation in almost parallel with cell cycles of normal embryos. The cell of colchicine-arrested embryos incorporated [3H]thymidine. Aphidicolin, a specific inhibitor of DNA synthesis, prevented cleavages of ascidian eggs. Embryos which had been permanently arrested with aphidicolin in the cleavage stages up to the 64-cell stage did not develop AChE activity, while embryos which had been treated with it from the 76-cell stage onwards were found to be able to differentiate AChE activity. Based on these findings it was proposed that DNA replication is prerequisite for development of the histospecific protein and that the cycle of DNA replication is closely associated with the clock mechanism which is determining the time of initiation of the enzyme development.

Acetylcholinesterase↗

PubMed2005

Circadian biology: clocks within clocks.

A small cluster of approximately 20,000 neurons in the ventral hypothalamus provide the body with key time-keeping signals and drive circadian rhythms. This circadian clock exhibits surprisingly complex substructures, with inputs from the retina, and outputs to other brain structures. Rather little is known of the neurotransmitters involved, or their regulation.

Animals↗

PubMed1984

The molecular clock may be an episodic clock.

It is argued that the apparent constancy of the rate of molecular evolution may be an artifact due to the very slow rate of evolution of individual amino acids. A statistical analysis of protein evolution using a stationary point process as the null hypothesis leads to the conclusion that molecular evolution is episodic, with short bursts of rapid evolution followed by long periods of slow evolution. Such dynamics are incompatible with the neutral allele theory and require a revision of the standard interpretation of the molecular clock.

Alleles↗

PubMed2006

Around the clock surveillance: simple graphic disturbance in patients with hemispatial neglect carries implications for the clock drawing task.

BACKGROUND: Drawing, and the clock drawing task in particular, is widely used as a diagnostic tool in the study of hemispatial neglect. It is generally assumed that the errors in graphic production, such as the misplacement of numbers, reflect a visuospatial deficit, and that drawing production itself (for example, producing the circle) is unimpaired. OBJECTIVES: To test this assumption by examining whether the production of simple circles is affected by neglect. METHODS: 16 right hemisphere stroke patients copied circles of various sizes and their drawings were measured for size accuracy. RESULTS: Patients with more severe neglect produced greater scaling errors, consistently drawing the circle smaller than the original. Errors were not in the horizontal axis alone--shrinkage occurred equally in both height and width axes. CONCLUSIONS: Neglect can co-occur with constructional difficulties that serve to exacerbate the symptoms presented. This should be taken into account in the assessment of even apparently simple drawing tasks.

Aged↗

PubMed2003