Tuning the Period of the Mammalian Circadian Clock: Additive and Independent Effects of CK1ε^Tauand Fbxl3^AfhMutations on Mouse Circadian Behavior and Molecular Pacemaking

Jan 29, 2011The Journal of neuroscience : the official journal of the Society for Neuroscience

Adjusting the body clock timing: separate and combined effects of two gene mutations on mouse daily rhythms and internal clock function

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Abstract

The mutations in male mice produced a spectrum of circadian periods for rest-activity behavior ranging from 20 to 28 hours.

Genetic differences in circadian pacemaking are linked to individual variances in sleep and metabolic disorders.
The individual stabilities of PER and CRY proteins influence the period of the circadian clock.
Interactions between mutations indicated that the stabilities of CRY and PER are regulated independently, contrary to previous assumptions.
The mutations had independent, additive effects on circadian period, favoring shorter periods driven by the CK1ε(Tau) mutation.
Alterations in the duration of the PER2-driven bioluminescence rhythm were observed, influenced by the competing effects of the two mutations.

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Circadian pacemaking in the suprachiasmatic nucleus (SCN) revolves around a transcriptional/posttranslational feedback loop in which period (Per) and cryptochrome (Cry) genes are negatively regulated by their protein products. Genetically specified differences in this oscillator underlie sleep and metabolic disorders, and dictate diurnal/nocturnal preference. A critical goal, therefore, is to identify mechanisms that generate circadian phenotypic diversity, through both single gene effects and gene interactions. The individual stabilities of PER or CRY proteins determine pacemaker period, and PER/CRY complexes have been proposed to afford mutual stabilization, although how PER and CRY proteins with contrasting stabilities interact is unknown. We therefore examined interactions between two mutations in male mice: Fbxl3(Afh), which lengthens period by stabilizing CRY, and Csnk1ε(tm1Asil) (CK1ε(Tau)), which destabilizes PER, thereby accelerating the clock. By intercrossing these mutants, we show that the stabilities of CRY and PER are independently regulated, contrary to the expectation of mutual stabilization. Segregation of wild-type and mutant alleles generated a spectrum of periods for rest-activity behavior and SCN bioluminescence rhythms. The mutations exerted independent, additive effects on circadian period, biased toward shorter periods determined by CK1ε(Tau). Notably, Fbxl3(Afh) extended the duration of the nadir of the PER2-driven bioluminescence rhythm but CK1ε(Tau) reversed this, indicating that despite maintained CRY expression, CK1ε(Tau) truncated the interval of negative feedback. These results argue for independent, additive biochemical actions of PER and CRY in circadian control, and complement genome-wide epistatic analyses, seeking to decipher the multigenic control of circadian pacemaking.

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Tuning the Period of the Mammalian Circadian Clock: Additive and Independent Effects of CK1ε^Tauand Fbxl3^AfhMutations on Mouse Circadian Behavior and Molecular Pacemaking

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