Fig. 1. Interlocked feedback loop model for Drosophila and mouse circadian oscillators. (A) Drosophila. The per/tim loop (left) and dClk loop (right) are shown. The model is based on data from peripheral oscillators. dCLK-CYC heterodimers activate per and tim transcription, and PER and TIM monomers accumulate in the cytoplasm and form heterodimers. PER-TIM then enters the nucleus, binds dCLK-CYC and inhibits the activation of per and tim, thus completing the per/tim feedback loop. dCLK-CYC dimers inhibit dClk transcription either directly (1a/1b) or indirectly via activation of a dClk repressor (2). Repression might occur through protein-DNA interaction (1a/2a) or protein-protein interaction (1b/2b). Repression of dClk is relieved when PER-TIM binds to dCLK-CYC, thus preventing this negative-feedback, and ensuring that per/tim and dClk mRNA transcripts cycle in anti-phase. Light input occurs through CRY, ultimately leading to the degradation of TIM. CRY can bind to TIM and PER, but whether CRY translocates to the nucleus with the PER-TIM dimer is not known. dClk repressor, gene that represses dClk transcription; dClk REPRESSOR, protein that represses dClk transcription; dClk ACTIVATOR, protein that activates dClk transcription. (B) Mouse. The mPer/mCry loop (left) and Bmal1 loop (right) are shown. The model is based on data from the SCN (black and green lines) and peripheral tissues (black, red and blue lines). mCLK-BMAL1 dimers activate mPer1, mPer2, mCry1 and mCry2 transcription, which is followed by the accumulation of mPERs and mCRYs in the cytoplasm. The mPERs bind to mCRYs and translocate to the nucleus. mCRYs and/or mPER2 then bind and inhibit mCLK-BMAL1, completing the mPer/mCry negative-feedback loop. Repression of Bmal1 transcription in peripheral tissues is mCLK-BMAL1 dependent. mCLK-BMAL1 might repress Bmal1 either directly through protein-DNA (1a) or protein-protein (1b) interaction, or indirectly by activating a Bmal1 repressor (2). The Bmal1 REPRESSOR may operate via protein-DNA (2a) or protein-protein (2b) interaction. Repression would then be relieved by mPER-mCRY-mediated inhibition of mCLK-BMAL1. In the SCN, mPER2 might co-activate Bmal1 by binding the Bmal1 ACTIVATOR (3a) or the Bmal1 REPRESSOR (3b). The figure is primarily based on in vivo data, since it is becoming increasingly evident that the interpretation of cell culture experiments is complicated by the presence of endogenous clock components (either expressed naturally or resulting from experimental manipulation). Bmal1 repressor, gene that represses Bmal1 transcription; Bmal1 REPRESSOR, protein that represses Bmal1 transcription; Bmal1 ACTIVATOR, protein that activates Bmal1 transcription.