Coupled oscillators in mammalian cells

Franck Delaunay
Université Côte d’Azur, CNRS, Inserm, iBV, France

Most organisms have evolved a circadian timing system to adapt their physiology and behaviour to the daily environmental changes resulting from the rotation of the earth on its axis. This is achieved through a self-sustained oscillatory gene network present in virtually all cells and which temporally coordinates a plethora of molecular, cellular and physiological processes. Interestingly, daily synchronous rhythms of the cell division cycle are observed in many species including humans. This strongly suggests that the circadian clock and the cell cycle machineries are functionally connected. Consistently, several molecular mechanisms underlying this crosstalk have been uncovered during the last 10-15 years. However, despite this mechanistic knowledge, how the temporal organization of cell division at the single cell level produces coherent daily rhythm at the tissue level and how the clock and cell cycle dynamics are coordinated have remained elusive. Using multispectral fluorescent imaging of genetically modified single live cells, computational methods and mathematical modelling we have addressed this issue in mouse fibroblastic cells. This approach revealed that in unsynchronized cells, the cell cycle and circadian clock robustly phase-lock each other in a 1:1 fashion so that in an expanding cell population the two oscillators oscillate in a synchronized way with a common frequency. Further, pharmacological synchronization of cellular clocks reveals additional phase-locked clock states. The temporal coordination of cell division by phase-locking to the clock at a single cell level has significant implications because circadian disruption is increasingly being linked to the pathogenesis of many diseases including metabolic diseases and cancer.