Function and regulation of the liver clock – from genes to behavior.

• Applicant: Professor Dr. Nicholas S. Foulkes
• Subject Area: Developmental Biology ; Evolutionary Cell and Developmental Biology (Zoology)
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 561162111

The daily timing of cellular, physiological and behavioral processes is vital for fitness and survival of most species. The circadian clock system directs this timing and is based on a network of molecular oscillators located in master clock organs, such as the hypothalamus, and peripheral organs such as the liver. Synchronization of the circadian clock system with the day-night cycle, predominantly by light and in some cases food availability, ensures that it remains synchronized with the environment. The ultimate goal of this proposed research is to understand how rhythms in the liver are regulated and how these affect behavioral rhythms. By developing and studying transgenic zebrafish lines, one of which lacks a circadian oscillator in the liver and another which possesses a functional circadian clock only in the liver, we will reveal the contribution of the liver circadian clock to behavioral rhythms in response to the prominent clock entraining signals - light-dark cycles and feeding time. Rhythmic gene expression in the liver of these transgenic animals, and of wildtype fish, will be analyzed in-vivo and ex-vivo, and rhythmic genes will be defined as being entrained by either feeding time or light-dark cycle, regulated by either liver-intrinsic clock or systemic cues, and by indirect or direct photoreception in the liver (a distinctive feature of fish cells). One centrally driven systemic signal that may regulate rhythmic gene expression in the liver is the night-time hormone, melatonin. To determine whether melatonin plays a role in regulating liver rhythmicity, rhythmic liver transcripts will be analyzed in genetically modified zebrafish lines which lack melatonin-producing cells or the melatonin producing enzyme. Combining our behavioral assay results with the associated changes in liver rhythmicity and regulation, we will obtain a holistic view of the liver within the complex circadian clock system in fish, and how it contributes to temporal regulation and fitness of the animal. The results of this project, including the novel genetic tools that we will develop, are expected to have a broad impact on both the chronobiology and physiology research fields.

• DFG Programme: Research Grants
• International Connection: Israel
• Partner Organisation: The Israel Science Foundation
• Cooperation Partner: Professor Dr. Yoav Gothilf, Ph.D.