Endocrine timing of the cell cycle in the zebrafish: The case of glucocorticoids

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Endocrine signals play crucial roles in normal physiology and disease. A major gap in our knowledge is how their rhythmic, often pulsatile release patterns impact on timing of their physiological targets in vivo, such as cell division cycles. Furthermore, relatively little is known about how these signalling systems mature functionally during development. Here, we propose to address these questions using glucocorticoids as an example of an endocrine signal. We will explore the molecular mechanisms underlying the recently revealed role of glucocorticoids in timing circadian cell cycle progression in zebrafish larvae [1] as a model physiological readout. We will use a set of biosensors to monitor glucocorticoid signalling activity and cell cycle progression in the intact animal to understand the dynamics of adrenal signals and their effect on cell cycle progression. Glucocorticoid signalling will be measured using a luciferase reporter under control of Glucocorticoid Response Elements, and cell cycle progression will be monitored using a luciferase reporter gene under control of the promoter of the cell cycle regulator Wee1. The biosensors will enable us to study the maturation of adrenal signalling and circadian cell cycle dynamics during development and in mutants with disrupted pituitary function. Ultimately, these biosensor lines will represent a valuable tool to screen for mutants with disrupted hypothalamic-pituitary-adrenal axis function and cell proliferation defects.