Abstract

The circadian (24 h) clock is continuously entrained (reset) by ambient light so that endogenous rhythms are synchronized with daily changes in the environment. Light-induced gene expression is thought to be the molecular mechanism underlying clock entrainment. mRNA translation is a key step of gene expression, but the manner in which clock entrainment is controlled at the level of mRNA translation is not well understood. We found that a light- and circadian clock–regulated MAPK/MNK pathway led to phosphorylation of the cap-binding protein eIF4E in the mouse suprachiasmatic nucleus of the hypothalamus, the locus of the master circadian clock in mammals. Phosphorylation of eIF4E specifically promoted translation of Period 1 (Per1) and Period 2 (Per2) mRNAs and increased the abundance of basal and inducible PER proteins, which facilitated circadian clock resetting and precise timekeeping. Together, these results highlight a critical role for light-regulated translational control in the physiology of the circadian clock.

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Acknowledgements

We thank D. Weaver, I. Edery and J. Stewart for advice and critical reading of the manuscript, and C. Zakaria, N. Robichaud, A. Sylvestre, B. Robinson and I. Harvey for excellent technical assistance. We are indebted to D. Weaver (University of Massachusetts Medical School) for his gift of the anti-PER1 serum and J. Takahashi (University of Texas Southwestern Medical Center) for his gift of the mPER2LUC transgenic mice. This work was supported by Canadian Institute of Health Research grants (MOP 114994 to N.S. and MOP 13625 to S.A.) and a US National Institutes of Health grant (NINDS R01NS054794 to A.C.L.). N.S. receives funding from the Howard Hughes Medical Institute. R.C. and N.d.Z. are recipients of the Fonds de recherche du Québec-Santé (FRQS) Postdoctoral Award and R.C. is a recipient of the Banting Postdoctoral Fellowship.

Author information

Affiliations

  1. Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montreal, Canada.

    • Ruifeng Cao
    • , Akiko Yanagiya
    • , Yoshinori Tsukumo
    •  & Nahum Sonenberg
  2. Patrick Wild Centre, Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK.

    • Christos G Gkogkas
  3. Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, Canada.

    • Nuria de Zavalia
    •  & Shimon Amir
  4. Douglas Mental Health University Institute and Department of Psychiatry, McGill University, Montreal, Quebec, Canada.

    • Ian D Blum
    •  & Kai-Florian Storch
  5. Department of Biological Sciences, University of Memphis, Memphis, Tennessee, USA.

    • Haiyan Xu
    •  & Andrew C Liu
  6. Department of Biomedical Sciences, Neuroscience Program, College of Medicine, Florida State University, Tallahassee, Florida, USA.

    • Choogon Lee

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Contributions

R.C., S.A. and N.S. designed the study. R.C., N.d.Z., C.G.G., I.D.B., Y.T., A.Y. and H.X. performed the experiments. C.L. and K.-F.S. contributed reagents and analytic tools. R.C., I.D.B., C.G.G., A.Y. and H.X. analyzed the data. R.C., A.C.L., S.A. and N.S. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Shimon Amir or Nahum Sonenberg.

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DOI

https://doi.org/10.1038/nn.4010

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