Abstract
BackgroundTGF-β signaling is a cellular pathway that functions in most cells and has been shown to play a role in multiple processes, such as the immune response, cell differentiation and proliferation. Recent evidence suggests a possible interaction between TGF-β signaling and the molecular circadian oscillator. The current study aims to characterize this interaction in the zebrafish at the molecular and behavioral levels, taking advantage of the early development of a functional circadian clock and the availability of light-entrainable clock-containing cell lines.ResultsSmad3a, a TGF-β signaling-related gene, exhibited a circadian expression pattern throughout the brain of zebrafish larvae. Both pharmacological inhibition and indirect activation of TGF-β signaling in zebrafish Pac-2 cells caused a concentration dependent disruption of rhythmic promoter activity of the core clock gene Per1b. Inhibition of TGF-β signaling in intact zebrafish larvae caused a phase delay in the rhythmic expression of Per1b mRNA. TGF-β inhibition also reversibly disrupted, phase delayed and increased the period of circadian rhythms of locomotor activity in zebrafish larvae.ConclusionsThe current research provides evidence for an interaction between the TGF-β signaling pathway and the circadian clock system at the molecular and behavioral levels, and points to the importance of TGF-β signaling for normal circadian clock function. Future examination of this interaction should contribute to a better understanding of its underlying mechanisms and its influence on a variety of cellular processes including the cell cycle, with possible implications for cancer development and progression.
Highlights
As a result of the earth’s rotation around its axis, the majority of organisms are exposed to rhythmic daily changes in their environment, including illumination, ambient temperature and food availability
Smad3a, a TGF-β signaling-related gene, exhibited a circadian expression pattern throughout the brain of zebrafish larvae. Both pharmacological inhibition and indirect activation of TGF-β signaling in zebrafish Pac-2 cells caused a concentration dependent disruption of rhythmic promoter activity of the core clock gene Per1b
Inhibition of TGF-β signaling in intact zebrafish larvae caused a phase delay in the rhythmic expression of Per1b mRNA
Summary
As a result of the earth’s rotation around its axis, the majority of organisms are exposed to rhythmic daily changes in their environment, including illumination, ambient temperature and food availability. A new cycle begins when Clock:Bmal repression is eliminated via the degradation of Per and Cry. A new cycle begins when Clock:Bmal repression is eliminated via the degradation of Per and Cry This core molecular mechanism affects other cellular functions by directing the circadian expression pattern of a variety of genes, collectively called clock-controlled genes (CCGs), which in turn regulate downstream processes. Some of these CCGs, for example Dec and Rev-erbα, feedback on the core clock mechanism itself [1,2,3,4]. The current study aims to characterize this interaction in the zebrafish at the molecular and behavioral levels, taking advantage of the early development of a functional circadian clock and the availability of light-entrainable clock-containing cell lines
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