A Clockwork Organ

Abstract

The vertebrate circadian clock was thought to be highly localized to specific anatomical structures: the mammalian suprachiasmatic nucleus (SCN), and the retina and pineal gland in lower vertebrates. However, recent findings in the zebrafish, rat and in cultured cells have suggested that the vertebrate circadian timing system may in fact be highly distributed, with most if not all cells containing a clock. Our understanding of the clock mechanism has progressed extensively through the use of mutant screening and forward genetic approaches. The first vertebrate clock gene was identified only a few years ago in the mouse by such an approach. More recently, using a syntenic comparative genetic approach, the molecular basis of the the tau mutation in the hamster was determined. The tau gene in the hamster appears to encode casein kinase 1 epsilon, a protein previously shown to be important for PER protein turnover in the Drosophila circadian system. A number of additional clock genes have now been described. These proteins appear to play central roles in the transcription-translation negative feedback loop responsible for clock function. Post-translational modification, protein dimerization and nuclear transport all appear to be essential features of how clocks are thought to tick.

Circadian rhythms from multiple oscillators: lessons from diverse organisms

“…Similar to D. melanogaster, peripheral oscillators in zebrafish (Danio rerio) and plants can be directly entrained by light. This indicates that they might not need a centralized pacemaker, as a principal function of such a pacemaker in mammals is to convert light entrainment signals from the eye into humoral signals that entrain peripheral tissues 142,143 . However, the potential for central oscillator function does exist in zebrafish, as pineal melatonin is produced in this species 31 .…”

Biological spacetime and the temporal integration of functional modules: A case study of dento–gnathic developmental timing

“…Other factors such as temperature and feeding times may finely tune local physiological rhythms, particularly in mammals (Damiola et al, 2000;Brown et al, 2002). Work on fly, fish, and rodent suggests that light cues entrain not only whole-body rhythms but also peripheral clocks in noncerebral body tissues and organs (Plautz et al, 1997;Whitmore et al, 1998Whitmore et al, , 2000aYamazaki et al, 2000;Yoo et al, 2004). Thus, in one organism, multiple largely synchronous circadian cycles fluctuate in various tissues by day and night.…”

“…Thus, in one organism, multiple largely synchronous circadian cycles fluctuate in various tissues by day and night. Of interest, it would seem that most every vertebrate cell has its own independently oscillating clock (Whitmore et al, 2000a). Furthermore, a given cell may contain more than one oscillatory cycle, each of which is regulated independently (Roenneberg and Morse, 1993).…”

Abnormal expressions of circadian-clock and circadian clock-controlled genes in the livers and kidneys of long-term, high-fat-diet-treated mice

“…Furthermore, casein kinase-1e (CK1e) protein is thought to phosphorylate the PER proteins, thereby enhancing their instability and degradation. [8][9][10][11] The CK1e protein also phosphorylates and partially activates the transcription factor, Bmal1. 9 Bmal1's expression is negatively regulated by the transcription factor reverse erythroblastosis virus-a (Rev-erb-a) 12 and positively regulated by retinoic acid-receptor-related orphan receptor-a (RORa) 13 via its response element.…”