Circadian rhythms, biological rhythms with a period of approximately 24 hours, appear to evolve from the adaptation of life to light/dark and temperature cycles on the Earth. Circadian rhythms have been observed among major phyla, from cyanobacteria, algae, fungi, plants, to animals, including insects, vertebrates such as fish, mouse, humans. Circadian rhythms appear be controlled by a self-sustained and autonomous clock. Conceptually, the circadian clock has three components as shown in the figure below:
The first one is an input pathway that links the internal cycle to external light-dark (and maybe temperature) cycles through photic or non-photic signal transduction pathways, which is largely unknown, but through which it is believed that the clock can be synchronized. The second is an autonomous, self-sustained and endogenous pacemaker or oscillator, which generates the circadian oscillations. The final one is an output pathway, which relays the circadian rhythmicity to overt physiological and behavioral rhythms. The process is also largely unknown. In other words, circadian clocks act like the watches and clocks you have: they are able to keep 24 hours a day, and when you travel to different time zones, they are able to adjust to the local time.The molecular genetic bases for circadian clocks appear conserved throughout evolution. Primarily through phenotype-driven forward genetics on the fruit fly, a circadian clock model has been formulated as shown below:
Primarily based upon molecular genetic works on Drosophila, a circadian clockwork model has been formulated. In the nucleus, shortly after noon, the CLOCK:CYCLE heterodimer binds the per and tim promoters through the E-boxes (CACGTG), and activates the transcription of per and tim. Messenger RNAs of per and tim are in turn transported into the cytoplasm and direct the synthesis of PER and TIM proteins. Light destroys TIM protein through a ubiquitin-mediated proteasomal pathway, whereas PER protein is phosphorylated by double time (a fly ortholog of mammalian casein kinase I epsilon, CKI epsilon) and kept inside the cytoplasm. Not until late evening, when light becomes dim, do TIM proteins accumulate. When TIM reaches a certain threshold, it binds PER and forms the PER:TIM heterodimer, which prevents PER from being phosphorylated. The TIM protein also helps translocate the PER:TIM heterodimer into the nucleus . Simply by binding the CLOCK:CYCLE heterodimer, the PER:TIM heterodimer represses the CLOCK:CYCLE heterodimer’s ability to bind the E boxes, and thereby inhibits the transcription of per and tim. Thus, this transcription/post translation-based feedback loop controls the circadian clock of fly. This is a simplified clockwork model. For instance, there is another feedback loop with VRI and PDP1 epsilon regulating clock in fly. In vertebrates such as the mouse, the similar transcription/post translation-based feedback loop also controls the circadian clocks, with CRYs capturing the function of TIM, whose circadian function is uncertain, and CK1e phosphorylating PERs. There also is a second loop with REV-ERB alpha and ROR alpha regulating transcription of bmal1. Furthermore, a growing number of genes have been discovered to regulate mammalian circadian rhythms, for instance, Fbxl3 directly regulating CRY and PERIOD proteins.
One of the driving forces behind circadian study is that we, as human being, suffer various circadian rhythm-related problems and diseases:
Insomnia, -- many people, particularly some elderly, cannot fall asleep in the night, which would definitely affect their next day's performance.
Jet lag -- people traveling to a different time zone, would soon or later suffer fatigue, most likely gastrointestinal complaints.
Shift work -- in America, approximately over 20% of working population have dealt with work shift.
It is our belief that by studying circadian clock genes and interactions between them, and particularly by studying animal circadian mutants, we could screen for drugs and provide cure for these human dysrhythmias.
