Abstract
Traveling waves play an essential role in coordinating mitosis over large distances, but what determines the spatial origin of mitotic waves remains unclear. Here, we show that such waves initiate at pacemakers, regions that oscillate faster than their surroundings. In cell-free extracts of Xenopus laevis eggs, we find that nuclei define such pacemakers by concentrating cell cycle regulators. In computational models of diffusively coupled oscillators that account for nuclear import, nuclear positioning determines the pacemaker location. Furthermore, we find that the spatial dimensions of the oscillatory medium change the nuclear positioning and strongly influence whether a pacemaker is more likely to be at a boundary or an internal region. Finally, we confirm experimentally that increasing the system width increases the proportion of pacemakers at the boundary. Our work provides insight into how nuclei and spatial system dimensions can control local concentrations of regulators and influence the emergent behavior of mitotic waves.
Highlights
Traveling waves are often used in nature to transmit information quickly and reliably over large distances (Cross and Hohenberg, 1993; Tyson and Keener, 1988; Gelens et al, 2014; Beta and Kruse, 2017; Deneke and Di Talia, 2018)
We have demonstrated that nuclei act as pacemakers generating the mitotic waves in Xenopus cell-free extracts
We built a generic computational model, which showed that the distribution of cell cycle regulators depends on the nuclear positioning and spatial dimensions of the system
Summary
Traveling waves are often used in nature to transmit information quickly and reliably over large distances (Cross and Hohenberg, 1993; Tyson and Keener, 1988; Gelens et al, 2014; Beta and Kruse, 2017; Deneke and Di Talia, 2018). We show that the generation of such pacemakers does not require centrosomes and explore the influence of nuclear density and nuclear import strength on cell cycle period and pacemaker wave formation Based on these observations, we develop a theoretical model where nuclei play an active role in concentrating cell cycle regulators. Our modeling shows that the distribution of regulators depends on the nuclear positioning and spatial dimensions of the system, with thicker tubes having a larger tendency to concentrate cell cycle regulators at the boundaries (i.e. outer edges of the tube) Using both numerical simulations and experiments, we go on to show that mitotic waves can originate from the system interior or from the system boundary, depending on the spatial dimensions of the system. These observed dynamics are the result of competition between waves originating from different pacemaker regions, where the relative strength of the pacemakers in the interior and at the boundary is determined by the system dimensions
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