Quantitative measures of clock protein dynamics in the mouse suprachiasmatic nucleus extends the circadian time-keeping model

The suprachiasmatic nucleus (SCN) synchronises circadian rhythmicity (~24 h) across the body. The SCN cell-autonomous clock is modelled qualitatively as a transcriptional-translational feedback loop (TTFL), with heteromeric complexes of transcriptional activator and repressor proteins driving cyclical gene expression. How these proteins really behave within the SCN, individually and in relation to each other, is poorly understood. Imaging SCN slices from a novel array of knock-in reporter mice, we quantify the dynamic behaviours of combined repressors PERIOD2 (PER2) and CRYPTOCHROME1 (CRY1), and activator BMAL1. We reveal a spectrum of protein-specific intracellular and spatiotemporal behaviours that run counter to the qualitative TTFL model. We also show that PER and CRY1 exert independent actions on TTFL oscillations, and that their individual stabilities play a critical role in SCN circadian dynamics. These results reveal a rich and unanticipated complexity in the dynamic behaviours and functions of endogenous circadian proteins, prompting re-appraisal of current transcriptional-translational feedback loop models of the suprachiasmatic nucleus.