The Circadian Clock Gates the Intestinal Stem Cell Regenerative State

• Published in: Cell reports (Cambridge) Vol. 3; no. 4; pp. 996 - 1004
• Main Authors: Karpowicz, Phillip, Zhang, Yong, Hogenesch, John B., Emery, Patrick, Perrimon, Norbert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.04.2013; Elsevier
• Subjects: Animals; Circadian Clocks; Circadian Rhythm; Drosophila - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Interphase; Intestines - cytology; Intestines - physiology; Period Circadian Proteins - genetics; Period Circadian Proteins - metabolism; Regeneration; Signal Transduction; Stem Cells - cytology; Stem Cells - metabolism; Transcription, Genetic
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.03.016

The intestine has evolved under constant environmental stresses, because an animal may ingest harmful pathogens or chemicals at any time during its lifespan. Following damage, intestinal stem cells (ISCs) regenerate the intestine by proliferating to replace dying cells. ISCs from diverse animals are remarkably similar, and the Wnt, Notch, and Hippo signaling pathways, important regulators of mammalian ISCs, are conserved from flies to humans. Unexpectedly, we identified the transcription factor period, a component of the circadian clock, to be critical for regeneration, which itself follows a circadian rhythm. We discovered hundreds of transcripts that are regulated by the clock during intestinal regeneration, including components of stress response and regeneration pathways. Disruption of clock components leads to arrhythmic ISC divisions, revealing their underappreciated role in the healing process. [Display omitted] •The circadian clock regulates regeneration in the fly gut•Circadian clocks are synchronized in stem cells and surrounding intestinal cells•The clock sensitizes stem cells to respond to damage The gut is subject to constant damage because animals ingest harmful pathogens and chemicals many times during their lives. When this happens, stem cells regenerate the gut quickly to replace dying cells. Karpowicz, Perrimon, and colleagues now find that regeneration is rhythmic and regulated by the widely conserved circadian clock. The clock synchronizes the behavior of animals to day/night cycles, and its disruption affects hundreds of genes in the intestine. These results show that gut healing fluctuates according to the time of day.