Light acts on the zebrafish circadian clock to suppress rhythmic mitosis and cell proliferation

A fundamental role of the circadian clock is to control biochemical and physiological processes such that they occur an optimal time of day. One of the most significant clock outputs from a clinical as well as basic biological standpoint is the timing of the cell cycle. Here we show that the circadian clock regulates the timing of mitosis in a light-responsive, clock-containing zebrafish cell line. Disrupting clock function, using a CLOCK1 dominant-negative construct or constant light, blocks the gating of cell division, demonstrating that this mitotic rhythm is cell autonomous and under control of the circadian pacemaker. Quantitative PCR reveals that several key mitotic genes, including Cyclin B1, Cyclin B2, and cdc2, are rhythmically expressed and clock-controlled. Peak expression of these genes occurs at a critical phase required to gate mitosis to the late night/early morning. Using clock and cell cycle luminescent reporter zebrafish cell lines, we show that light strongly represses not only circadian clock function, but also mitotic gene expression, and consequently slows cell proliferation.