  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. 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. 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.
