Interactions between the circadian clock and TGF-β signaling pathway in zebrafish

• Published in: PloS one 2018-06, Vol.13 (6), p.e0199777-e0199777
• Main Authors: Sloin, Hadas E, Ruggiero, Gennaro, Rubinstein, Amir, Smadja Storz, Sima, Foulkes, Nicholas S, Gothilf, Yoav
• Format: Article
• Language: English
• Subjects: Biochemistry; Biology and Life Sciences; Biophysics; Brain; Cancer; Cell cycle; Cell differentiation; Circadian rhythm; Circadian rhythms; Clock gene; CLOCK protein; Clock systems; Danio rerio; Differentiation (biology); Feedback; Gene expression; Immune response; Immune system; Inhibition; Kinases; Larvae; Life sciences; Locomotor activity; Molecular chains; mRNA; Neurobiology; Neurosciences; Pharmacology; Physiology; Proteins; Research and Analysis Methods; Signal transduction; Signaling; Toxicology; Zebrafish
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0199777

TGF-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. 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. TGF-β inhibition also reversibly disrupted, phase delayed and increased the period of circadian rhythms of locomotor activity in zebrafish larvae. The 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.