Noise-resistant and synchronized oscillation of the segmentation clock

Abstract

Periodic somite segmentation in vertebrate embryos is controlled by the 'segmentation clock', which consists of numerous cellular oscillators. Although the properties of a single oscillator, driven by a hairy negative-feedback loop, have been investigated, the system-level properties of the segmentation clock remain largely unknown. To explore these characteristics, we have examined the response of a normally oscillating clock in zebrafish to experimental stimuli using in vivo mosaic experiments and mathematical simulation. We demonstrate that the segmentation clock behaves as a coupled oscillator, by showing that Notch-dependent intercellular communication, the activity of which is regulated by the internal hairy oscillator, couples neighbouring cells to facilitate synchronized oscillation. Furthermore, the oscillation phase of individual oscillators fluctuates due to developmental noise such as stochastic gene expression and active cell proliferation. The intercellular coupling was found to have a crucial role in minimizing the effects of this noise to maintain coherent oscillation.

Modelling Oscillator Synchronisation During Vertebrate Axis Segmentation

“…If so, the order parameter could be measured by relating the activity of the reporter to a nominally defined 'phase' and using (2) to measure global synchrony. The effects of perturbations to global synchrony, such as the qualitative experiments performed by Horikawa et al [3], could then be measured experimentally and the resulting order parameter data could be directly compared with theoretical models, such as (1).…”

“…Using zebrafish, Horikawa et al [3] observed that cells which were either in, or had just recently exited, M phase of the cell cycle tended to be out of phase with neighbouring oscillators in the posterior PSM. They concluded that during M phase of the cell cycle the transcription necessary to progress the somitogenesis clock was paused as the cells prepared for division, thus dividing cells drifted out of phase with their neighbours.…”

“…Synchronisation within the PSM is also perturbed by mitosis: when a cell enters M phase of the cell cycle it ceases the transcription necessary to progress its somitogenesis clock [3,8]. Thus, when the cell divides both mother and daughter cells are out of phase with their neighbours.…”

“…Notch-Delta signalling is a key cell-cell communication mechanism in the PSM [1,2] and it is thought that one of its roles is to synchronise the oscillations of neighbouring oscillators [3]. However, mutants for different Delta ligands are observed to affect oscillation patterns in the PSM in different ways, suggesting more than the single role of synchronisation in the PSM for Notch-Delta signalling [4,5], or at the very least a complex interaction between Notch-Delta signalling components and the somitogenesis clock.…”

From segment to somite: Segmentation to epithelialization analyzed within quantitative frameworks

“…More recently, Horikawa and colleagues investigated the coupling of segmentation clocks within individual PSM cells by means of Notch-dependent intercellular communication regulated by the internal hairy oscillator. They showed, using a combination of experimental methods and modeling, that this could lead to synchronized oscillations robust to the presence of noise (Horikawa et al, 2006).…”