Glucocorticoids Play a Key Role in Circadian Cell Cycle Rhythms

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Abstract
Clock output pathways play a pivotal role by relaying timing information from the circadian clock to a diversity of physiological systems. Both cell-autonomous and systemic mechanisms have been implicated as clock outputs; however, the relative importance and interplay between these mechanisms are poorly understood. The cell cycle represents a highly conserved regulatory target of the circadian timing system. Previously, we have demonstrated that in zebrafish, the circadian clock has the capacity to generate daily rhythms of S phase by a cell-autonomous mechanism in vitro. Here, by studying a panel of zebrafish mutants, we reveal that the pituitary–adrenal axis also plays an essential role in establishing these rhythms in the whole animal. Mutants with a reduction or a complete absence of corticotrope pituitary cells show attenuated cell-proliferation rhythms, whereas expression of circadian clock genes is not affected. We show that the corticotrope deficiency is associated with reduced cortisol levels, implicating glucocorticoids as a component of a systemic signaling pathway required for circadian cell cycle rhythmicity. Strikingly, high-amplitude rhythms can be rescued by exposing mutant larvae to a tonic concentration of a glucocorticoid agonist. Our work suggests that cell-autonomous clock mechanisms are not sufficient to establish circadian cell cycle rhythms at the whole-animal level. Instead, they act in concert with a systemic signaling environment of which glucocorticoids are an essential part. To guarantee normal growth and to avoid tumor formation, the timing of cell division must be under strict control. Remarkably, cells, from bacteria to man, often divide only at certain times of day, suggesting the influence of internal biological clocks. A central pacemaker structure in the brain controls diurnal rhythms of behavior and hormone release. However, biological clocks are also encountered in almost every cell type (so-called “peripheral” clocks), in which they regulate daily changes in cell biology, including cell division. Very little is known to date about how the two clock systems interact. Here, by examining zebrafish strains with defects in hormone production, we find that peripheral clocks require the steroid hormone cortisol to generate daily rhythms of cell proliferation. Interestingly, the daily changes in cortisol levels observed in normal zebrafish are not required to achieve this control; treating the cortisol-deficient strains with constant levels of a drug that mimics the effects of cortisol restores normal cell-division rhythms. Thus, it appears that internal cell timers cooperate with hormonal signals to regulate the timing of cell division.