title: Intercellular coupling regulates the period of the segmentation clock.
abstract: BACKGROUND
  Coupled biological oscillators can tick with the same period. How this collective period is established is a key question in understanding biological clocks. We explore this question in the segmentation clock, a population of coupled cellular oscillators in the vertebrate embryo that sets the rhythm of somitogenesis, the morphological segmentation of the body axis. The oscillating cells of the zebrafish segmentation clock are thought to possess noisy autonomous periods, which are synchronized by intercellular coupling through the Delta-Notch pathway. Here we ask whether Delta-Notch coupling additionally influences the collective period of the segmentation clock.
  
  
  RESULTS
  Using multiple-embryo time-lapse microscopy, we show that disruption of Delta-Notch intercellular coupling increases the period of zebrafish somitogenesis. Embryonic segment length and the spatial wavelength of oscillating gene expression also increase correspondingly, indicating an increase in the segmentation clock's period. Using a theory based on phase oscillators in which the collective period self-organizes because of time delays in coupling, we estimate the cell-autonomous period, the coupling strength, and the coupling delay from our data. Further supporting the role of coupling delays in the clock, we predict and experimentally confirm an instability resulting from decreased coupling delay time.
  
  
  CONCLUSIONS
  Synchronization of cells by Delta-Notch coupling regulates the collective period of the segmentation clock. Our identification of the first segmentation clock period mutants is a critical step toward a molecular understanding of temporal control in this system. We propose that collective control of period via delayed coupling may be a general feature of biological clocks.
authors.affiliation: Max Planck Institute for Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
authors.forename: Leah
authors.initials: L
authors.lastname: Herrgen
authors.forename: Saúl
authors.initials: S
authors.lastname: Ares
authors.forename: Luis G
authors.initials: LG
authors.lastname: Morelli
authors.forename: Christian
authors.initials: C
authors.lastname: Schröter
authors.forename: Frank
authors.initials: F
authors.lastname: Jülicher
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Oates
mesh_terms: D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D019521:Body Patterning / Q000502:physiology*; D003198:Computer Simulation; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019170:Somites / Q000502:physiology*; D013997:Time Factors; D015027:Zebrafish / Q000196:embryology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; C064045:delta protein