Targeted modification of the Per2 clock gene alters circadian function in mPer2luciferase (mPer2Luc) mice

Ralph, Martin R.; Shi, Shu-qun; Johnson, Carl Hirschie; Houdek, Pia; Shrestha, Tenjin C.; Crosby, Priya; O’Neill, John S.; Sládek, Martin; Stinchcombe, Adam R.; Sumová, Alena

doi:10.1371/journal.pcbi.1008987

Cited by 8 publications

(6 citation statements)

References 75 publications

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“…S6A and S6B, see also Ralph et al, 2021). Male mPer2 Luc mice have been reported to display a greater predisposition to display bimodal locomotor rhythms relative to male C57Bl/6 mice (Ralph et al, 2021), but we did not observe a difference in the duration of the nightly siesta in male mice from each line (Suppl. Fig.…”

Section: Discussionmentioning

confidence: 86%

Biological Sex Influences Daily Locomotor Rhythms in Mice Held Under Different Housing Conditions

Pastrick,

Diaz,

Adaya

et al. 2024

J Biol Rhythms

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Daily rhythms are programmed by a central circadian clock that is modulated by photoperiod. Here, we recorded locomotor activity rhythms in C57Bl/6 or mPer2Luc mice of both sexes held under different housing conditions. First, we confirm that the structure of locomotor activity rhythms differs between male and female mice in both genetic backgrounds. Male mice exhibit a nightly “siesta,” whereas female mice fluctuate between nights with and without a nightly siesta, which corresponds with changes in locomotor activity levels, circadian period, and vaginal cytology. The nightly siesta is modulated by the presence of a running wheel in both sexes but is not required for the infradian patterning of locomotor rhythms in females. Finally, photoperiodic changes in locomotor rhythms differed by sex, and females displayed phase-jumping responses earlier than males under a parametric photoentrainment assay simulating increasing day length. Collectively, these results highlight that sex and sex hormones influence daily locomotor rhythms under a variety of different environmental conditions.

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Section: Discussionmentioning

confidence: 86%

Biological Sex Influences Daily Locomotor Rhythms in Mice Held Under Different Housing Conditions

Pastrick,

Diaz,

Adaya

et al. 2024

J Biol Rhythms

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“…Mice homozygous for a targeted allele of Dbp have only a modest circadian phenotype (Lopez-Molina et al, 1997). Homozygotes of both the Per2 LucSV and Per2 Luciferase lines have altered circadian rhythms (Ralph et al, 2021; Yoo et al, 2017; see below). The GFP-expressing Dbp transcript lacks the native 3′ UTR and uses an exogenous polyadenylation sequence, which could affect Dbp gene expression and regulation.…”

Section: Discussionmentioning

confidence: 99%

“…The potential impact of a single Per2 LucSV allele (as used in our studies) on period length has not been reported, but this could contribute to the longer period of Per2 LucSV/+ explants, relative to Dbp Luc/+ explants. Interestingly, Ralph et al (2021) recently reported that the Per2 Luciferase reporter that uses the endogenous Per2 3′UTR (Yoo et al, 2004) also has longer period in DD and other circadian phenotypes. Tosini and colleagues have also recently reported retinal degeneration and alterations in classical photoreception in aged male Per2 Luciferase/Luciferase mice (Goyal et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Cell-Type-Specific Circadian Bioluminescence Rhythms inDbpReporter Mice

et al. 2022

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Circadian rhythms are endogenously generated physiological and molecular rhythms with a cycle length of about 24 h. Bioluminescent reporters have been exceptionally useful for studying circadian rhythms in numerous species. Here, we report development of a reporter mouse generated by modification of a widely expressed and highly rhythmic gene encoding D-site albumin promoter binding protein ( Dbp). In this line of mice, firefly luciferase is expressed from the Dbp locus in a Cre recombinase-dependent manner, allowing assessment of bioluminescence rhythms in specific cellular populations. A mouse line in which luciferase expression was Cre-independent was also generated. The Dbp reporter alleles do not alter Dbp gene expression rhythms in liver or circadian locomotor activity rhythms. In vivo and ex vivo studies show the utility of the reporter alleles for monitoring rhythmicity. Our studies reveal cell-type-specific characteristics of rhythms among neuronal populations within the suprachiasmatic nuclei ex vivo. In vivo studies show Dbp-driven bioluminescence rhythms in the liver of Albumin-Cre;Dbp KI/+ “liver reporter” mice. After a shift of the lighting schedule, locomotor activity achieved the proper phase relationship with the new lighting cycle more rapidly than hepatic bioluminescence did. As previously shown, restricting food access to the daytime altered the phase of hepatic rhythmicity. Our model allowed assessment of the rate of recovery from misalignment once animals were provided with food ad libitum. These studies confirm the previously demonstrated circadian misalignment following environmental perturbations and reveal the utility of this model for minimally invasive, longitudinal monitoring of rhythmicity from specific mouse tissues.

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“…For organotypic SCN slice culture from heterozygous PER2::LUC knock-in mice (Yoo et al, 2004), 2-4 months old mice were used in VIP application experiments and P11-14 mice were used in optogenetic stimulation experiments. We used heterozygous PER2::LUC mice as the PER2::LUC knock-in allele can alter circadian functions such as free-running period (Ralph et al, 2021). All animals were housed in a 12:12 light-dark cycle (except as noted), and had food and water provided ad libitum.…”

Section: Methodsmentioning

confidence: 99%

DNA methylation is a widespread mechanism of light-induced circadian clock period plasticity

Kim

McMahon

2022

Preprint

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The suprachiasmatic nucleus (SCN) of the hypothalamus is a principal light-responsive circadian clock that adjusts circadian rhythms in mammalian physiology and behavior to changes in external light signals. Although mechanisms underlying how light acutely resets the timing of circadian rhythms have been characterized, it remains elusive how light signals induce lasting changes in circadian period, so-called period after-effects. Here we have found that the period after-effects on circadian behavior of changing photoperiods are blocked by application of DNA methyltransferase inhibitors directed to the SCN. At the level of single light pulses that act as clock-resetting stimulations, pharmacologically inhibiting DNA methylation in the SCN significantly attenuates period after-effects following acute phase shifts in behavioral rhythms in vivo, and blocks period after-effects on clock gene rhythms in the isolated ex vivo SCN. Acute clock resetting shifts themselves, however, do not appear to require DNA methylation at the SCN and behavioral levels, in contrast to subsequent period plasticity. Our results indicate that DNA methylation in the SCN mediates light-induced period after-effects in response to photoperiods, and single light pulses, and together with previous studies showing that DNA methylation in the SCN is essential for period after-effects of non-24hr light cycles (T-cycles), suggest that DNA methylation in the SCN is a widespread mechanism of light-induced circadian period plasticity.

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Targeted modification of the Per2 clock gene alters circadian function in mPer2luciferase (mPer2Luc) mice

Cited by 8 publications

References 75 publications

Biological Sex Influences Daily Locomotor Rhythms in Mice Held Under Different Housing Conditions

Biological Sex Influences Daily Locomotor Rhythms in Mice Held Under Different Housing Conditions

Cell-Type-Specific Circadian Bioluminescence Rhythms inDbpReporter Mice

DNA methylation is a widespread mechanism of light-induced circadian clock period plasticity

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