Glucocorticoids Play a Key Role in Circadian Cell Cycle Rhythms

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.

Cross-talks between Circadian Timing System and Cell Division Cycle Determine Cancer Biology and Therapeutics

“…Molecular clocks in healthy cells control the cell division cycle through Clock:Bmal1 regulation of several key cell cycle genes (Fu and Lee 2003;Matsuo et al 2003). Circadian physiology can also and redundantly regulate cell cycle traverse (Dickmeis et al 2007).…”

Circadian rhythms in Mexican blind cavefish Astyanax mexicanus in the lab and in the field

“…Independent circadian clocks are found in virtually all zebrafish tissues, and these tissues are themselves directly light responsive 18,19 . Light signals have a strong impact, not only on resetting of the zebrafish circadian clock [20][21][22] , but also on numerous aspects of zebrafish cell biology, such as the activation of DNA repair processes [23][24][25][26] and the regulation of cell cycle events [27][28][29][30] . Evolving in a completely dark environment is therefore likely to impact fish physiology in a dramatic manner.…”

Glucocorticoids and circadian clock control of cell proliferation: At the interface between three dynamic systems

“…Our own studies have revealed a role for glucocorticoids in the regulation of circadian rhythms of cell proliferation in zebrafish larvae [161]. Circadian cell cycle rhythms can be observed both in larvae and in zebrafish-derived cell lines, implying that cell-autonomous clock regulation also exists in this species [162].…”

“…Circadian cell cycle rhythms can be observed both in larvae and in zebrafish-derived cell lines, implying that cell-autonomous clock regulation also exists in this species [162]. However, in vivo, systemic input is also required: in mutants lacking a pituitary gland, cell cycle rhythms are severely attenuated [161]. Subsequent analysis of mutants that lack subsets of the pituitary cell types identified the corticotrope lineage as the source for the required signal.…”

“…Interface A-C: Depending on the cell type, glucocorticoids can both inhibit and enhance cell proliferation in a variety of systems. They are required for circadian cell cycle progression in zebrafish larvae, thereby connecting all three systems [161]. For details see text.…”