Glucocorticoids play a key role in circadian cell cycle rhythms.
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.
Dickmeis
Thomas
T
Max-Planck-Institut für Entwicklungsbiologie, Tübingen, Germany.
Lahiri
Kajori
K
Nica
Gabriela
G
Vallone
Daniela
D
Santoriello
Cristina
C
Neumann
Carl J
CJ
Hammerschmidt
Matthias
M
Foulkes
Nicholas S
NS
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D049109:Cell Proliferation; D002940:Circadian Rhythm; D006854:Hydrocortisone / Q000502:physiology*; D008969:Molecular Sequence Data; D009154:Mutation; D015027:Zebrafish
D006854:Hydrocortisone