Abstract
In mammals, the principal circadian oscillator exists in the hypothalamic suprachiasmatic nucleus (SCN). In the SCN, CLOCK works as an essential component of molecular circadian oscillation, and ClockΔ19 mutant mice show unique characteristics of circadian rhythms such as extended free running periods, amplitude attenuation, and high-magnitude phase-resetting responses. Here we investigated what modifications occur in the spatiotemporal organization of clock gene expression in the SCN of ClockΔ19 mutants. The cultured SCN, sampled from neonatal homozygous ClockΔ19 mice on an ICR strain comprising PERIOD2::LUCIFERASE, demonstrated that the Clock gene mutation not only extends the circadian period, but also affects the spatial phase and period distribution of circadian oscillations in the SCN. In addition, disruption of the synchronization among neurons markedly attenuated the amplitude of the circadian rhythm of individual oscillating neurons in the mutant SCN. Further, with numerical simulations based on the present studies, the findings suggested that, in the SCN of the ClockΔ19 mutant mice, stable oscillation was preserved by the interaction among oscillating neurons, and that the orderly phase and period distribution that makes a phase wave are dependent on the functionality of CLOCK.
Highlights
Our internal clock mechanism, named the circadian clock, governs daily variations in many metabolic, physiologic, and behavioral functions[1]
Spontaneous activity was measured in Clock mutant mice on an ICR genetic background entrained to 12 h-light/12 h-dark cycles, and showed a long free-running period under constant darkness
When the intercellular communication that maintains synchrony among oscillation neurons in the suprachiasmatic nucleus (SCN) was blocked, the oscillation of the whole SCN and individual cells showed much lower circadian bioluminescence rhythms (Figs 3 and 4). These findings suggest that the SCN is equipped with a molecular system of intercellular communication that compensates for the dysfunction of the circadian locomotor output cycles kaput (CLOCK) protein, which is an essential component for circadian transcriptional translational feedback
Summary
Our internal clock mechanism, named the circadian clock, governs daily variations in many metabolic, physiologic, and behavioral functions[1]. Accumulated PER and CRY proteins form a complex that represses the transcriptional activity of the CLOCK/BMAL1 heterodimer This autoregulatory loop builds an oscillation of gene expression approximately 24 h in duration. The mutant mice exhibit abnormally long periodicity of spontaneous activity under constant environments, and slightly decreased contrast between the light-period and the dark-period in activity and feeding under a light-dark cycle Their phase-shifting responses to light pulses in circadian activity rhythms are much larger than that of wild-type mice[14,15]. In vivo and in vitro, the circadian clock in the SCN of ClockΔ19 mutant mice exhibits long periodicity, attenuation of gene expression that depends on the E-box transcriptional cis-element, and high-amplitude phase-resetting responses[14,15,16,17,18]. Gene ablation of Rgs[16] impaired normal spatiotemporal organization of clock genes in the SCN, and lengthened the circadian period of behavioral rhythms[25]
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