Cellular signalling and the complexity of biological timing: insights from the ultradian clock ofSchizosaccharomyces pombe

Abstract

The molecular bases of circadian clocks are complex and cannot be su¤ciently explained by the relatively simple feedback loops, based on transcription and translation, of current models. The existence of additional oscillators has been demonstrated experimentally, but their mechanism(s) have so far resisted elucidation and any universally conserved clock components have yet to be identi¢ed. The ¢ssion yeast, Schizosaccharomyces pombe, as a simple and well-characterized eukaryote, is a useful model organism in the investigation of many aspects of cell regulation. In fast-growing cells of the yeast an ultradian clock operates, which can serve as a model system to analyse clock complexity. This clock shares strict period homeostasis and e¤cient entrainment with circadian clocks but, because of its short period of 30 min, mechanisms other than a transcription/translation-based feedback loop must be working. An initial systematic screen involving over 200 deletion mutants has shown that major cellular signalling pathways (calcium/phosphoinositide, mitogen-activated protein kinase and cAMP/protein kinase A) are crucial for the normal functioning of this ultradian clock. A comparative examination of the role of cellular signalling pathways in the S. pombe ultradian clock and in the circadian timekeeping of di¡erent eukaryotes may indicate common principles in biological timing processes that are universally conserved amongst eukaryotes.

Timing in Cellular Ca2+ Signaling

“…These fluctuations encompass rhythmic changes in baseline Ca 2+ observed in fungi, plants and animals [66-69], upon which are superimposed stimulation-evoked Ca 2+ transients that occur episodically as bursts of oscillations or repetitive Ca 2+ spikes with regulable intermittency [3,70] and cell-/agonist- specific profiles [71]. The duration of trains of Ca 2+ spikes (which can be evoked for hours in experiments) is physiologically significant [72].…”

Emergence of self-organised oscillatory domains in fungal mycelia

“…On this basis it is more plausible to propose that pulsing arises from a metabolic oscillator, uncoupled from any genetic pacemaker (Kippert, 2001;Lloyd and Murray, 2005;Lloyd, 2006). Recently, however, the conceptual separation between circadian-linked oscillators and metabolic oscillators has become less distinct.…”

Fourier-based spatial mapping of oscillatory phenomena in fungi

“…Microorganisms display a range of rhythmic phenomena with different periods ranging from ultradian metabolic and transcriptional oscillators in yeast (Kippert, 2001;Lloyd and Murray, 2005;Lloyd, 2006;Reinke and Gatfield, 2006), through pulsatile growth of Physarum (Ueda, 2005), cAMP-dependent signalling waves during aggregation in Dictyostelium (Sawai et al, 2005;Dormann and Weijer, 2006), to the canonical temperature-compensated circadian oscillators in Neurospora (Lakin- Thomas and Brody, 2004;Bell-Pedersen et al, 2005;Dunlap, 2006;Lakin-Thomas, 2006a;Lakin-Thomas, 2006b;Liu and Bell-Pedersen, 2006). When there is no explicit spatial dimension to the oscillation, analysis of the rhythm can be captured by the average response of the system and presented as a simple graph of the time-series (Priestley, 1981;Diggle, 1990;Smith, 1997;Chatfield, 2004), provided the sampling interval itself does not introduce aliasing artifacts (Gilbert and Ferreira, 2000).…”