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.

[1]  T. Tamai,et al.  Light signaling to the zebrafish circadian clock by Cryptochrome 1a , 2007, Proceedings of the National Academy of Sciences.

[2]  D. Whitmore,et al.  Imaging of single light-responsive clock cells reveals fluctuating free-running periods , 2005, Nature Cell Biology.

[3]  Carl Hirschie Johnson,et al.  Circadian clocks and cell division , 2010, Cell cycle.

[4]  Shin Yamazaki,et al.  Circadian-independent cell mitosis in immortalized fibroblasts , 2010, Proceedings of the National Academy of Sciences.

[5]  F. Halberg.  Temporal coordination of physiologic function. , 1960, Cold Spring Harbor symposia on quantitative biology.

[6]  Jeffrey C. Hall,et al.  A Mutant Drosophila Homolog of Mammalian Clock Disrupts Circadian Rhythms and Transcription of period and timeless , 1998, Cell.

[7]  Minoru Tanaka,et al.  Positional Cloning of the Mouse Circadian Clock Gene , 1997, Cell.

[8]  Paolo Sassone-Corsi,et al.  Zebrafish Clock rhythmic expression reveals independent peripheral circadian oscillators , 1998, Nature Neuroscience.

[9]  Francis Lévi,et al.  Host circadian clock as a control point in tumor progression. , 2002, Journal of the National Cancer Institute.

[10]  Steve A. Kay,et al.  Bioluminescence Imaging of Individual Fibroblasts Reveals Persistent, Independently Phased Circadian Rhythms of Clock Gene Expression , 2004, Current Biology.

[11]  U. Schibler,et al.  A Serum Shock Induces Circadian Gene Expression in Mammalian Tissue Culture Cells , 1998, Cell.

[12]  David Whitmore,et al.  E-box function in a period gene repressed by light , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Felix Naef,et al.  Circadian Gene Expression in Individual Fibroblasts Cell-Autonomous and Self-Sustained Oscillators Pass Time to Daughter Cells , 2004, Cell.

[14]  Anne-Marie Chang,et al.  Functional Identification of the Mouse Circadian Clock Gene by Transgenic BAC Rescue , 1997, Cell.

[15]  T. Dickmeis,et al.  Glucocorticoids Play a Key Role in Circadian Cell Cycle Rhythms , 2007, PLoS biology.

[16]  D. Weaver,et al.  Disrupting the circadian clock: Gene-specific effects on aging, cancer, and other phenotypes , 2011, Aging.

[17]  M. Antoch,et al.  Disruption of the circadian clock due to the Clock mutation has discrete effects on aging and carcinogenesis , 2008, Cell cycle.

[18]  S. Gery,et al.  Circadian rhythms and cancer , 2010, Cell cycle.

[19]  Franck Delaunay,et al.  Effects of Chronic Jet Lag on Tumor Progression in Mice , 2004, Cancer Research.

[20]  Paolo Sassone-Corsi,et al.  Common pathways in circadian and cell cycle clocks: light-dependent activation of Fos/AP-1 in zebrafish controls CRY-1a and WEE-1. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[21]  David Whitmore,et al.  Light Regulates the Cell Cycle in Zebrafish , 2003, Current Biology.

[22]  R. Baler,et al.  Circadian Transcription , 2002, The Journal of Biological Chemistry.

[23]  松尾 拓哉.  Control mechanism of the circadian clock for timing of cell division in vivo , 2004 .

[24]  Paolo Sassone-Corsi,et al.  Light acts directly on organs and cells in culture to set the vertebrate circadian clock , 2000, Nature.

[25]  Francis J. Doyle,et al.  Intercellular Coupling Confers Robustness against Mutations in the SCN Circadian Clock Network , 2007, Cell.

[26]  Steven A. Brown,et al.  Resetting of circadian time in peripheral tissues by glucocorticoid signaling. , 2000, Science.

[27]  David Whitmore,et al.  Autonomous onset of the circadian clock in the zebrafish embryo , 2008, The EMBO journal.

[28]  C. Allis,et al.  Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation , 1997, Chromosoma.

[29]  Tony Hunter,et al.  Isolation of a human cyclin cDNA: Evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2 , 1989, Cell.

[30]  Erin L. McDearmon,et al.  Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation , 2007, Proceedings of the National Academy of Sciences.