The circadian clock is a widespread cellular mechanism that underlies diverse rhythmic functions in organisms from bacteria and fungi, to plants and animals. Intense genetic analysis during recent years has uncovered many of the components and molecular mechanisms comprising these clocks. Although autoregulatory genetic networks are a consistent feature in the design of all clocks, the weight of evidence favours their independent evolutionary origins in different kingdoms.

Time zones: a comparative genetics of circadian clocks.

In this era of jet travel, our body 'remembers' the previous time zone, such that when we travel, our sleep wake pattern, mental alertness, eating habits and many other physiological processes temporarily suffer the consequences of time displacement until we adjust to the new time zone. Although the existence of a circadian clock in humans had been postulated for decades, an understanding of the molecular mechanisms has required the full complement of research tools. To gain the initial insights into circadian mechanisms, researchers turned to genetically tractable model organisms such as Drosophila.

Circadian rhythms from flies to human

Cryptochromes are flavoprotein photoreceptors first identified in Arabidopsis thaliana, where they play key roles in growth and development. Subsequently identified in prokaryotes, archaea, and many eukaryotes, cryptochromes function in the animal circadian clock and are proposed as magnetoreceptors in migratory birds. Cryptochromes are closely structurally related to photolyases, evolutionarily ancient flavoproteins that catalyze light-dependent DNA repair. Here, we review the structural, photochemical, and molecular properties of cry-DASH, plant, and animal cryptochromes in relation to biological signaling mechanisms and uncover common features that may contribute to better understanding the function of cryptochromes in diverse systems including in man.

The Cryptochromes: Blue Light Photoreceptors in Plants and Animals

Intercellular Coupling Confers Robustness against Mutations in the SCN Circadian Clock Network

Rhythms of mammalian body temperature can sustain peripheral circadian clocks.

Cryptochromes are flavin/pterin-containing proteins that are involved in circadian clock function in Drosophila and mice. In mice, the cryptochromes Cry1 and Cry2 are integral components of the circadian oscillator within the brain and contribute to circadian photoreception in the retina. In Drosophila, cryptochrome (CRY) acts as a photoreceptor that mediates light input to circadian oscillators in both brain and peripheral tissue. A Drosophila cry mutant, cryb, leaves circadian oscillator function intact in central circadian pacemaker neurons but renders peripheral circadian oscillators largely arrhythmic. Although this arrhythmicity could be caused by a loss of light entrainment, it is also consistent with a role for CRY in the oscillator. A peripheral oscillator drives circadian olfactory responses in Drosophila antennae. Here we show that CRY contributes to oscillator function and physiological output rhythms in the antenna during and after entrainment to light-dark cycles and after photic input is eliminated by entraining flies to temperature cycles. These results demonstrate a photoreceptor-independent role for CRY in the periphery and imply fundamental differences between central and peripheral oscillator mechanisms in Drosophila.

A new role for cryptochrome in a Drosophila circadian oscillator

Although transcriptional regulation is a major force in generating circadian oscillations of clock molecules, posttranscriptional mechanisms also contribute to molecular rhythms. Applying novel transgenic period-luciferase constructs in transgenic Drosophila, the authors show that sequences within per's 5'-untranslated region mediate posttranscriptional regulation at the RNA level. Further mapping suggests that the relevant sequences for the correct phasing of period mRNA expression are located within the first intron. The results are consistent with a clock-regulated temporal stabilization of period mRNA during its daily upswing in the morning. This process is inferred to depend on a function of the PERIOD and TIMELESS proteins, and could further contribute to the observed delay between RNA and protein accumulation. Similarly, applying timeless-luciferase constructs led to the demonstration that regulatory elements for proper temporal timeless expression are present in a 4 kb promoter fragment and in sequences within the first intron. The results establish that, for normal rhythmicity, expression of clock genes requires regulation at the transcriptional, posttranscriptional, and posttranslational levels.

M. Kathlea S. Lynch

Papers

A new role for cryptochrome in a Drosophila circadian oscillator

Mapping of Elements Involved in Regulating Normal Temporal period and timeless RNA Expression Patterns in Drosophila melanogaster