Reppert, at Massachusetts General Hospital at the time, and his team showed that the murine circadian clock is orchestrated by positive and negative transcription and post-translation feedback loops. Using mutant mice, they found that the Period2 protein positively regulates the Bmal1 gene loop, and that cryptochrome proteins negatively regulate the Period and Cryptochrome loops. The Takahashi lab paper showed that a mutation of a specific kinase that modifies circadian clock proteins has a clear effect on the mammalian circadian clock.
Reppert surmised that "there is this discrepancy between the molecular alterations in Cryptochrome-deficient mice and Period 2-deficient animals that we thought could be explained by a second loop." The other factor the team considered is the clock's two essential transcription factors, Clock and Bmal1. Bmal1 is known to be rhythmic and its rhythm is out of phase with the Period and Cryptochrome genes. "Bells went off," Reppert remembers. The investigators ...
