The tau Mutation in the Syrian Hamster Differentially Reprograms the Circadian Clock in the SCN and Peripheral Tissues

Abstract

The hypothalamic suprachiasmatic nuclei (SCN), the principal circadian oscillator in mammals, are synchronized to the solar day by the light-dark cycle, and in turn, they coordinate circadian oscillations in peripheral tissues. The tau mutation in the Syrian hamster is caused by a point mutation leading to a deficiency in the ability of Casein Kinase 1epsilon to phosphorylate its targets, including circadian PER proteins. How this accelerates circadian period in neural tissues is not known, nor is its impact on peripheral circadian oscillators established. We show that this mutation has no effect on per mRNA expression nor the nuclear accumulation of PER proteins in the SCN. It does, however, accelerate the clearance of PER proteins from the nucleus to an extent sufficient to explain the shortened circadian period of behavioral rhythms. The mutation also has novel, unanticipated consequences for circadian timing in the periphery, including tissue-specific phase advances and/or reduced amplitude of circadian gene expression. The results suggest that the tau mutation accelerates a specific phase, during mid-late subjective night of the SCN circadian feedback loop, rather than cause a global compression of the entire cycle. This reprogrammed output from the clock is associated with peripheral desynchrony, which in turn could account for impaired growth and metabolic efficiency of the mutant.

Role of Phosphorylation in the Mammalian Circadian Clock

“…3) (Vanselow et al 2006). This result is similar to observations for PER1 and PER2 in the SCN of tau mutant hamsters (Dey et al 2005). Thus, phosphorylation at the FASPS region increases nuclear retention of PER2, thereby protecting it from cytoplasmic degradation by the proteasome.…”

“…Because phosphorylation triggers degradation, it has been assumed that PER hypophosphorylation would lead to a stabilization of PER proteins and thus to a more rapid PER accumulation in the cytoplasm, followed by an advanced nuclear localization of PER proteins. An earlier repression of CLOCK-BMAL1 transcriptional activity then would lead to shorter circadian periods (Lowrey et al 2000;Dey et al 2005). However, we propose an alternative mechanism (see below).…”

“…Unexpectedly, however, tau mutant hamsters exhibit robust circadian rhythms in both PER protein abundance and PER phosphorylation without substantial differences in the degree of hyperphosphorylation, although the overall amount of PER protein is reduced (Lee et al 2001). Interestingly, an accelerated nuclear clearance of PER proteins in the SCN of tau mutant hamsters has been reported (Dey et al 2005).…”

“…With respect to the tau mutation, our model and that of Gallego et al (2006b) offer alternative but not mutually exclusive explanations. We favor a mechanism where a reduced kinase activity of mutant CKIε leads to an altered, less nuclear localization of PER proteins (as observed by Dey et al 2005). Because phosphorylation-induced proteasomal degradation of PER proteins is primarily a cytosolic event (Vanselow et al 2006), the overall phosphorylation of the PER proteins in tau hamsters may even increase (as observed by Gallego et al 2006b).…”

“…The tau mutation was discovered by Ralph and Menaker (1988) on the basis of a prominent shortening of the circadian locomotor activity rhythm-a 22-hour period in heterozygous animals and a 20-hour period in homozygous animals (Ralph and Menaker 1988). The mRNA profiles of Per1 and Per2 in the SCN (suprachiasmatic nucleus) of tau mutant hamsters show an earlier rise and decline and a reduction in the peak expression levels of both genes (Lowrey et al 2000;Dey et al 2005). Genetic analysis revealed that a singlenucleotide exchange in the coding region of the CKIε gene generates the tau mutant phenotype.…”