Molecular Analysis of Mammalian Circadian Rhythms

Abstract

In mammals, a master circadian "clock" resides in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN clock is composed of multiple, single-cell circadian oscillators, which, when synchronized, generate coordinated circadian outputs that regulate overt rhythms. Eight clock genes have been cloned that are involved in interacting transcriptional-/translational-feedback loops that compose the molecular clockwork. The daily light-dark cycle ultimately impinges on the control of two clock genes that reset the core clock mechanism in the SCN. Clock-controlled genes are also generated by the central clock mechanism, but their protein products transduce downstream effects. Peripheral oscillators are controlled by the SCN and provide local control of overt rhythm expression. Greater understanding of the cellular and molecular mechanisms of the SCN clockwork provides opportunities for pharmacological manipulation of circadian timing.

Novel functions for Period 3 and Exo-rhodopsin in rhythmic transcription and melatonin biosynthesis within the zebrafish pineal organ

“…Per proteins typically regulate the timing of gene expression by repressing gene transcription [44]. Consistent with this, we found that exorh transcripts were up-regulated during the day in embryos injected with a per3 MO ( Figure 3B, C).…”

“…While the functions of vertebrate Per1 and Per2 proteins are well established, the function of Per3 has been difficult to define. In mice, Per1 and Per2 have central roles in the feedback loops of the circadian clock and in resetting the clock in response to environmental light cues [44]. In contrast, per3 knock out mice have only a slight decrease in the period of their circadian clock [51].…”

Circadian genes, rhythms and the biology of mood disorders

“…The primary molecular clock is located in the suprachiasmatic nucleus (SCN) in the hypothalamus, and consists of a transcriptional feedback loop which cycles over the course of approximately twenty-four hours in the absence of environmental input (Reppert and Weaver, 2001; Ko and Takahashi, 2006). The major transcriptional activator consists of a dimer between the Circadian Locomotor Output Cycles Kaput Protein (CLOCK) and Brain and Muscle ARNT-like Protein 1 (BMAL1, also known as ARNTL or MOP3).…”

“…Daily rhythms are prominent in everything from sleep/wake cycles, body temperature, hormone levels, and even cognition, attention and mood (Bunney and Bunney, 2000;Reppert and Weaver, 2001). Disruptions in biological rhythms are known to be strongly associated with mood disorders.…”

Differential effects of constant light on circadian clock resetting by photic and nonphotic stimuli in Syrian hamsters

“…In the mouse, for example, clock and bmall form a promoter complex driving the expression of clock and clock controlled genes. PERI-3 proteins, phosphorylated via casein kinase IE (CKIE), form heterodimers with CRY1 and CRY2 proteins in the cytoplasm, allowing nuclear trans location^ and negative feedback on gene transcription (Dunlap, 1999;Okamura et al, 2002;Preitner etal., 2002;Reppert & Weaver, 2001). This mechanism results in a self-sustained oscillation of clock and clock controlled gene e:wpression.…”