Circadian Rhythms in Animals: A Canonical Connections Map

Abstract

Circadian rhythms are near-24-hour endogenous rhythms of behavior and physiology that are a nearly universal feature of eukaryotic life. Genetic and biochemical experiments over the past decade have allowed the construction of a viable working model for the molecular mechanisms underlying circadian rhythm generation in animals. The basic mechanism consists of two intertwined transcription-translation negative feedback loops. One loop--the "positive loop"--controls the rhythmic expression of a well-conserved Per-Arnt-Sim (PAS)-domain-containing positive transcription factor (Clock in Drosophila, and BMAL1, which is also known as MOP3, in the mouse). The second loop--the "negative loop"--controls the expression of another PAS-domain protein (the repressor Period), as well as species-specific repressors (Timeless in Drosophila and Cryptochrome in mice). The loops are intertwined because Period and its binding partners directly repress transcription mediated by Clock and its binding partners (Cycle in Drosophila and BMAL1 in the mouse), whereas Clock:Cycle (or CLOCK:BMAL1) drives the transcription of period and the other repressors, as well as that of repressors of Clock or Bmal1 transcriptional expression. Other factors, including conserved kinases such as Casein kinase I ϵ (CkIϵ), have essential functions in the timekeeping mechanism. Remarkably, this mechanism appears to be fundamentally conserved between Drosophila and mammalian circadian clocks. This Canonical Connections Map Pathway describes the basic mechanism underlying circadian signaling, whereas the accompanying specific Pathway Maps for Drosophila and murine circadian mechanisms describe the individual known components of the circadian clock and their mutual interactions. Science Viewpoint R. N. Van Gelder, E. D. Herzog, W. J. Schwartz, P. H. Taghert, Circadian rhythms: In the loop at last. Science 300, 1534-1535 (2003). [Abstract] [Full Text]