Nuclei determine the spatial origin of mitotic waves

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.

The nucleus serves as the pacemaker for the cell cycle

“…2-figure supplement 1). This phenomenon has been noted previously in studies of mitotic trigger waves and apoptotic trigger waves in Xenopus extracts (16,32), and it is seen in mathematical models of trigger waves as well (41). Thus, there are at least two types of sources: nuclear sources and edge sources.…”

Synchronizing an oscillatory medium: The speed of pacemaker-generated waves

“…The biochemical underpinnings of these cell cycle oscillations are well characterized. Moreover, in extracts made of these frog eggs, waves of mitosis have been observed [12], and recently the importance of pacemakers in these systems has been shown as well [26,27].…”

“…In such chemical systems, pacemakers can appear through impurities such as dust particles, or they can be induced, for example, to suppress chaotic behavior [22]. In biological systems, target patterns occur in cyclic adenosine monophosphate (cAMP) signaling in Dictyostelium discoideum [23], cardiac tissue [18], yeast glycolysis [24], neural tissue [25], and cell-free extracts of Xenopus laevis frog eggs [12], where nuclei act as pacemakers to organize the dynamics [26,27]. Pacemaker-generated waves have a clear function in these biological systems: they synchronize the system over long distances and transmit information inside the cell or between cells [1,11,16].…”

Dynamic bistable switches enhance robustness and accuracy of cell cycle transitions

“…Waves of Cdk1 activity spread throughout the cell at mitotic entry, as has been observed in Xenopus cell-free extracts [65, 66] and in the early Drosophila embryo [67, 68]. In the cell, and in extracts, spatial heterogeneities are present through nuclei, which concentrate certain proteins [66].…”

“…Models that include a spatial component often focus on traveling waves which can play a role in synchronizing large cells, such as Xenopus embryos [65] or Drosophila syncytia [67]. In Xenopus cell-free extracts, nuclei play an essential role as a pacemaker, possibly due to the fact that nuclei locally increase concentrations of key regulatory proteins, in turn changing the bistable switch upon which mitotic entry is built [66]. In Drosophila , changes to the bistable switch have been proposed as an explanation of changing wavespeeds over different cycles [67], and bistable thresholds play a crucial role in the so-called sweep waves [68].…”