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Rigid Cooperation of Per1 and Per2 proteins

View Article: PubMed Central - PubMed

ABSTRACT

Period circadian clock (Per) genes Per1 and Per2 have essential roles in circadian oscillation. In this study, we identified a new role of Per1-Per2 cooperation, and its mechanism, using our new experimental methods. Under constant light conditions, the period length of Per1 and Per2 knockout mice depended on the copy number ratio of Per1:Per2. We then established a light-emitting diode-based lighting system that can generate any pattern of light intensity. Under gradually changing light in the absence of phase shift with different periods, both Per1(−/−) and Per2(−/−) mice were entrained to a broader range of period length than wild-type mice. To analyse Per1-Per2 cooperative roles at the cell culture level, we established a Per2 knockout-rescue system, which can detect period shortening in a familial advanced sleep phase syndrome (FASPS) mutant. Upon introduction of the Per1 coding region in this system, we saw period shortening. In conclusion, short period-associated protein Per1 and long period-associated Per2 cooperated to rigidly confine the circadian period to “circa” 24-h. These results suggest that the rigid circadian rhythm maintained through the cooperation of Per1-Per2 could negatively impact modern society, in which the use of artificial lighting is ubiquitous, and result in circadian disorders, including delirium.

No MeSH data available.


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Arrhythmicity under conditions of constant light was not likely to occur when either Per1 or Per2 was deficient.(A) Number and genotype of mice used in this experiment. (B) Schematic diagram of the experimental procedure. Six mice of each genotype were used in each (a and b) crossover design experiment. Animals were exposed to the indicated number of hours of light and/or dark for the indicated number of days. The light intensity was within the range of 100–300 Lux in the light phase at the centre bottom of the cage. (C) Representative actogram for each genotype. (D) Periodicity is defined as the mean amplitude (Q[p]) minus the level of significance at the determined period length within ±1 h of the circadian period length, determined using the chi-square periodogram. Values represent mean ± standard deviation (SD) of a single experiment. P-values were calculated using one-way ANOVA and Tukey’s post hoc tests. The F and P-values from the Tukey’s test are shown in Supplemental Table S3.
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f2: Arrhythmicity under conditions of constant light was not likely to occur when either Per1 or Per2 was deficient.(A) Number and genotype of mice used in this experiment. (B) Schematic diagram of the experimental procedure. Six mice of each genotype were used in each (a and b) crossover design experiment. Animals were exposed to the indicated number of hours of light and/or dark for the indicated number of days. The light intensity was within the range of 100–300 Lux in the light phase at the centre bottom of the cage. (C) Representative actogram for each genotype. (D) Periodicity is defined as the mean amplitude (Q[p]) minus the level of significance at the determined period length within ±1 h of the circadian period length, determined using the chi-square periodogram. Values represent mean ± standard deviation (SD) of a single experiment. P-values were calculated using one-way ANOVA and Tukey’s post hoc tests. The F and P-values from the Tukey’s test are shown in Supplemental Table S3.

Mentions: Prolonged periods of constant light are known to cause arrhythmicity, which may mimic circadian disorders, including delirium. To observe the effect of constant light-induced arrhythmicity in Per knockout mice, we first synchronized the mice under conditions of a 12-h light/12-h dark cycle for 14 days. We then exposed WT Per1(+/+)Per2(+/+), Per1(−/−), and Per2(−/−) mice (n = 12/group) to constant light for 28 days, analysed locomotor activities, and calculated the periodicity (Fig. 2A,B). Although WT mice gradually became arrhythmic with constant light for more than 14 days, Per1(−/−) and Per2(−/−) mice maintained rhythmicity (Fig. 2C,D). That is, arrhythmic change under conditions of constant light is not likely to occur if either Per1 or Per2 are deficient.


Rigid Cooperation of Per1 and Per2 proteins
Arrhythmicity under conditions of constant light was not likely to occur when either Per1 or Per2 was deficient.(A) Number and genotype of mice used in this experiment. (B) Schematic diagram of the experimental procedure. Six mice of each genotype were used in each (a and b) crossover design experiment. Animals were exposed to the indicated number of hours of light and/or dark for the indicated number of days. The light intensity was within the range of 100–300 Lux in the light phase at the centre bottom of the cage. (C) Representative actogram for each genotype. (D) Periodicity is defined as the mean amplitude (Q[p]) minus the level of significance at the determined period length within ±1 h of the circadian period length, determined using the chi-square periodogram. Values represent mean ± standard deviation (SD) of a single experiment. P-values were calculated using one-way ANOVA and Tukey’s post hoc tests. The F and P-values from the Tukey’s test are shown in Supplemental Table S3.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5016722&req=5

f2: Arrhythmicity under conditions of constant light was not likely to occur when either Per1 or Per2 was deficient.(A) Number and genotype of mice used in this experiment. (B) Schematic diagram of the experimental procedure. Six mice of each genotype were used in each (a and b) crossover design experiment. Animals were exposed to the indicated number of hours of light and/or dark for the indicated number of days. The light intensity was within the range of 100–300 Lux in the light phase at the centre bottom of the cage. (C) Representative actogram for each genotype. (D) Periodicity is defined as the mean amplitude (Q[p]) minus the level of significance at the determined period length within ±1 h of the circadian period length, determined using the chi-square periodogram. Values represent mean ± standard deviation (SD) of a single experiment. P-values were calculated using one-way ANOVA and Tukey’s post hoc tests. The F and P-values from the Tukey’s test are shown in Supplemental Table S3.
Mentions: Prolonged periods of constant light are known to cause arrhythmicity, which may mimic circadian disorders, including delirium. To observe the effect of constant light-induced arrhythmicity in Per knockout mice, we first synchronized the mice under conditions of a 12-h light/12-h dark cycle for 14 days. We then exposed WT Per1(+/+)Per2(+/+), Per1(−/−), and Per2(−/−) mice (n = 12/group) to constant light for 28 days, analysed locomotor activities, and calculated the periodicity (Fig. 2A,B). Although WT mice gradually became arrhythmic with constant light for more than 14 days, Per1(−/−) and Per2(−/−) mice maintained rhythmicity (Fig. 2C,D). That is, arrhythmic change under conditions of constant light is not likely to occur if either Per1 or Per2 are deficient.

View Article: PubMed Central - PubMed

ABSTRACT

Period circadian clock (Per) genes Per1 and Per2 have essential roles in circadian oscillation. In this study, we identified a new role of Per1-Per2 cooperation, and its mechanism, using our new experimental methods. Under constant light conditions, the period length of Per1 and Per2 knockout mice depended on the copy number ratio of Per1:Per2. We then established a light-emitting diode-based lighting system that can generate any pattern of light intensity. Under gradually changing light in the absence of phase shift with different periods, both Per1(−/−) and Per2(−/−) mice were entrained to a broader range of period length than wild-type mice. To analyse Per1-Per2 cooperative roles at the cell culture level, we established a Per2 knockout-rescue system, which can detect period shortening in a familial advanced sleep phase syndrome (FASPS) mutant. Upon introduction of the Per1 coding region in this system, we saw period shortening. In conclusion, short period-associated protein Per1 and long period-associated Per2 cooperated to rigidly confine the circadian period to “circa” 24-h. These results suggest that the rigid circadian rhythm maintained through the cooperation of Per1-Per2 could negatively impact modern society, in which the use of artificial lighting is ubiquitous, and result in circadian disorders, including delirium.

No MeSH data available.


Related in: MedlinePlus