Regulation of tissue regeneration by the circadian clock.

Circadian rhythms are regulated by a highly conserved transcriptional/translational feedback loop that maintains approximately 24-hr periodicity from cellular to organismal levels. Much research effort is being devoted to understanding how the outputs of the master clock affect peripheral oscillators, and in turn, numerous biological processes. Recent studies have revealed roles for circadian timing in the regulation of numerous cellular behaviours in support of complex tissue regeneration. One such role involves the interaction between the circadian clockwork and the cell cycle. The molecular mechanisms that control the cell cycle create a system of regulation that allows for high fidelity DNA synthesis, mitosis and apoptosis. In recent years, it has become clear that clock gene products are required for proper DNA synthesis and cell cycle progression, and conversely, elements of the cell cycle cascade feedback to influence molecular circadian timing mechanisms. It is through this crosstalk that the circadian system orchestrates stem cell proliferation, niche exit and control of the signalling pathways that govern differentiation and self-renewal. In this review, we discuss the evidence for circadian control of tissue homeostasis and repair and suggest new avenues for research.

Photoresponsivity and motility in the planarian Schmidtea mediterranea vary diurnally.

The planarian flatworm has become one of the leading animal model systems for studying stem cell behavior and tissue regeneration. Recent studies have shown that components of the circadian clockwork have important roles in tissue homeostasis and repair. However, it remains unknown whether planarians exhibit circadian or diurnal rhythms in physiology or behavior. Here, we developed a behavioral assay to evaluate diurnal activity in planarians based upon their well-established propensity to swim away from light (negative phototaxis). We show evidence that the planarian Schmidtea mediterranea has diurnal variability in negative phototaxis as a function of daily variation in motility. We also demonstrate that variation in planarian motility over 48 h occurs with 24-h periodicity. Our data suggest that S. mediterranea may be a useful model for studying the interplay between the circadian system and tissue regeneration.

A circadian clock regulates sensitivity to cadmium in Paramecium tetraurelia.

The heavy metal cadmium is a dangerous environmental toxicant that can be lethal to humans and other organisms. This paper demonstrates that cadmium is lethal to the ciliated protozoan Paramecium tetraurelia and that a circadian clock modulates the sensitivity of the cells to cadmium. Various concentrations of cadmium were shown to increase the number of behavioral responses, decrease the swimming speed of cells, and generate large vacuole formation in cells prior to death. Cells were grown in either 12-h light/12-h dark or constant dark conditions exhibited a toxic response to 500 microM CdCl(2); the sensitivity of the response was found to vary with a 24-h periodicity. Cells were most sensitive to cadmium at circadian time 0 (CT0), while they were least sensitive in the early evening (CT12). This rhythm persisted even when the cells were grown in constant dark. The oscillation in cadmium sensitivity was shown to be temperature-compensated; cells grown at 18 degrees C and 28 degrees C had a similar 24-h oscillation. Finally, phase shifting experiments demonstrated a phase-dependent response to light. These data establish the criteria required for a circadian clock and demonstrate that P. tetraurelia possesses a circadian-influenced regulatory component of the cadmium toxic response. The Paramecium system is shown to be an excellent model system for the study of the effects of biological rhythms on heavy metal toxicity.