The circadian clock is the mechanism that coordinates an organism's internal rhythms with daily changes in the environment. To maintain synchronicity, the clock is continuously reset or entrained by signals from the environment, primarily light. But the molecular basis of clock entrainment is not well understood. A new study directed by Shimon Amir of Concordia University and Nahum Sonenberg of McGill University, both in Montreal, Canada, brings to light the process by which entrainment is controlled at the level of mRNA translation. “This study is the first to reveal a mechanism that explains how light regulates protein synthesis in the brain, and how this affects the function of the circadian clock,” noted Sonenberg in a press release.

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The scientists focused on the protein eIF4E, which has a key role in initiating mRNA translation and can be regulated by phosphorylation. In mice, eIF4E was phosphorylated in the brain region that houses the mammalian master circadian clock. Furthermore, phosphorylation of eIF4E was regulated by light and by the circadian clock. The research team then engineered the brains of mice to express a mutant version of eIF4E that could not be phosphorylated. Mice with mutant eIF4E did not respond appropriately to manipulations of the light:dark cycle, which included exposure to constant darkness with occasional light pulses or to altered circadian periods of 21 h, 22 h, 26 h or 27 h (Nat. Neurosci. 18, 855–862; 2015). Finally, they found that translation and expression of the period proteins Per1 and Per2, which facilitate clock entrainment, were dependent on phosphorylation of eIF4E. Taken together, the results show that phosphorylation of eIF4E in response to light and circadian cycling promotes translation of Per1 and Per2 and thus has an essential role in the physiology of the mammalian circadian clock.

Dysregulation of the circadian clock is associated with a range of behavioral, cognitive and metabolic disorders, including sleep disturbances. Such disorders are commonly associated with jet lag and shift work and also occur in some neuropsychiatric conditions like depression and autism. Understanding the molecular processes underlying clock entrainment might lead to new ways of treating these diseases. Amir stated, “Disruption of the circadian rhythm is sometimes unavoidable but it can lead to serious consequences. This research is really about the importance of the circadian rhythm to our general well-being. We've taken an important step towards being able to reset our internal clocks—and improve the health of thousands as a result.”