The Biology of the Circadian Ck1εtauMutation in Mice and Syrian Hamsters: A Tale of Two Species

Abstract

INTRODUCTIONThe past decade has witnessed spectacular advances in our understanding of the genetic basis of circadian timing in mammals. The circadian pacemakers within the suprachiasmatic nucleus (SCN) of the hypothalamus provide a crucial function in conducting a circadian repertoire throughout the body, acting on peripheral oscillators in all major body organs and tissues, with profound effects on general systemic physiology (Reppert and Weaver 2002;Hastings et al. 2003;Lowrey and Takahashi 2004;Saper et al. 2005). In both brain and periphery, the molecular clockwork operates as a series of interlocked autoregulatory feedback loops in which CLOCK:BMAL1 heterodimers bind to E-box DNA sequences contained within genes encoding transcriptional repressors PER and CRY. Following their accumulation in the cytoplasm, PER:CRY complexes translocate to the nucleus after a delay of several hours and repress the activity of constitutively bound CLOCK:BMAL1 complexes. These inhibitory complexes are then degraded following a further delay, and the consequent derepression of CLOCK:BMAL1 activity initiates the next circadian cycle of Per and Cry transcription.We have now come to recognize the all-pervasive nature of circadian timing in biology, and the next challenge is to unravel the mechanisms and pathways involved in mediating the effects of the clocks on physiology and metabolism. The general prevalence of many diseases is also marked by a strong circadian component in morbidity, and circadian mutants are often characterized by unexpected side effects in a wide range of pathologies, including malignancy and metabolic and cardiovascular defects. Mutations in various elements of this core molecular clock have been described, many of which result in either arrhythmia or alteration in period of rest/activity and sleep cycles. Genetically mediated desynchronization of central pacemaker function is also strongly implicated as the primary causal mechanism of familial advanced sleep phase syndrome (FASPS), and unraveling the complexities of how circadian mutations act on both central and peripheral pacemakers will reveal important new insight into both the normal regulation of sleep and the pathologies associated with sleep disruption.As in many areas of biology, much of our recent understanding has come from the use of genetically modified mice, allowing studies of incredible sophistication in a species that has an "amenable" genome. Many of the chapters in this volume are devoted to a detailed exposition of the molecular regulation of circadian timing and the impact of clocks on both normal physiology and disease processes. Here, we describe the biology of the first bona fide circadian mutation ever discovered in a mammal, the tau mutation of the Syrian hamster. We explore the impact that this timing mutation has on both the daily and seasonal biology of this species and then describe the same mutation in genetically modified mice. Here, we are able to use the power of mouse genetics to demonstrate some unexpected features of t...

Natural selection against a circadian clock gene mutation in mice

“…It was first detected in Syrian hamsters (Mesocricetus auratus), where it causes τ to shorten with ∼2 h for each copy of the mutant allele (11). In mice, the same mutation shortens the circadian cycle to an almost identical extent (10). As a consequence of the accelerated circadian clockwork, both homozygote tau mice and hamsters are unable to entrain to 24-h LD cycles in the laboratory.…”

“…The Ck1e tau (hereafter defined as the tau mutation) is a gain-offunction mutation (7) that accelerates the cellular dynamics of the circadian PERIOD protein (8,9) and affects circadian behavior and physiology (10). It was first detected in Syrian hamsters (Mesocricetus auratus), where it causes τ to shorten with ∼2 h for each copy of the mutant allele (11).…”

Energy-responsive timekeeping

“…Interestingly, the SIRT1 agonist resveratrol induces the phosphorylation and activation of AMPK (Baur et al 2006;Dasgupta and Milbrandt 2007), and activation of AMPK induces NAMPT transcription during glucose restriction (Fulco et al 2008). AMPK has recently been shown to heighten the activity of casein kinase 1ε (CK1ε) (Um et al 2007), an enzyme central to determining the period of clock transcriptional feedback loops (Gallego and Virshup 2007;Loudon et al 2007;Meng et al 2008). …”

Translational Regulation of the DOUBLETIME/CKIδ/ε Kinase by LARK Contributes to Circadian Period Modulation

“…Casein kinase I (CKI) is required for period determination in vertebrates as well as insects. For example, in hamster and mouse, a gain-of-function mutation of CKIε ( CKIε tau ), causes shortening of circadian period [24], [25] whereas inhibition of CKIδ kinase activity in zebrafish disrupts circadian rhythmicity in locomotor activity [26]. In humans, a mutation in the key clock protein PERIOD 2 perturbs its phosphorylation by CKIε and is associated with Familial Advanced Sleep Phase Syndrome (FASPS), as a result of an abnormally short circadian period [27]–[31].…”