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Activation of TGF-β/activin signalling resets the circadian clock through rapid induction of Dec1 transcripts

Nature Cell Biology volume 10, pages 1463–1469 (2008)Cite this article

Abstract

The circadian clock is reset by external time cues for synchronization to environmental changes1. In mammals, the light-input signalling pathway mediated by Per gene induction has been extensively studied2,3. On the other hand, little is known about resetting mechanisms that are independent of Per induction4,5,6. Here we show that activation of activin receptor-like kinase (ALK), triggered by TGF-β, activin or alkali signals, evoked resetting of the cellular clock independently of Per induction. The resetting was mediated by an immediate-early induction of Dec1, a gene whose physiological role in the function of the circadian clock has been unclear. Acute Dec1 induction was a prerequisite for ALK-mediated resetting and upregulation was dependent on SMAD3, which was phosphorylated for activation in response to the resetting stimuli. Intraperitoneal injection of TGF-β into wild-type or Dec1-deficient mice demonstrated that Dec1 has an essential role in phase-shift of clock gene expression in the kidney and adrenal gland. These results indicate that ALK–SMAD3–Dec1 signalling provides an input pathway in the mammalian molecular clock.

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Figure 1: A pHo shock resets cellular rhythm in cultured Rat-1 fibroblasts.
Figure 2: Immediate induction of Dec1 transcripts is essential for resetting of the cellular rhythm by the alkaline shock.
Figure 3: Activation of ALK pathway by alkaline shock induces Dec1 transcripts and resets the cellular rhythm.
Figure 4: Activation of TGF-β/activin signalling pathway induces Dec1 transcripts and resets the cellular clock.
Figure 5: Activation of the TGF-β signalling pathway induces Dec1 transcripts and resets peripheral clock in vivo.

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Acknowledgements

We thank T. Okano for valuable discussion; K. Sanada and H. Yoshitane for comments on the manuscripts; M. Akiyama for providing pGL3-Basic-Hyg reporter vector; K. Ui-Tei and Y. Naito for technical advice on RNA interference; M. Takekawa for technical advice for experiment with kinase inhibitors. This work was supported in part by Grants-in-Aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology, by the 21st Century COE Program (Promotion of basic biosciences for the understanding of organisms' uniqueness), and by Global COE Program (Integrative Life Science Based on the Study of Biosignaling Mechanisms) from MEXT, Japan.

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Authors and Affiliations

  1. Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, 113-0033, Tokyo, Japan

    Naohiro Kon, Tsuyoshi Hirota, Tadashi Tsubota & Yoshitaka Fukada

  2. Department of Dental and Medical Biochemistry, Hiroshima University Graduate School of Biomedical Sciences, 734-8553, Hiroshima, Japan

    Takeshi Kawamoto & Yukio Kato

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  1. Naohiro Kon
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Contributions

N. K. and T. H. developed the real-time monitoring assay system; N. K. performed the cell biological and animal experiments with assistance from T. H and Y. F.; T. K. and Y. K. generated Dec1−/− mice; T. T. quantified TGF-β by ELISA with assistance from N. K and Y. F; N. K., T. H. and Y. F. planned the project and wrote the manuscript.

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Correspondence to Yoshitaka Fukada.

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Kon, N., Hirota, T., Kawamoto, T. et al. Activation of TGF-β/activin signalling resets the circadian clock through rapid induction of Dec1 transcripts. Nat Cell Biol 10, 1463–1469 (2008). https://doi.org/10.1038/ncb1806

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