Nuclei determine the spatial origin of mitotic waves
- KU Leuven, Belgium
- University of California San Francisco, United States
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 which 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, influencing the emergent behavior of mitotic waves.
Data availability
All the data generated during the study are summarized and provided in the manuscript and supporting files. Source files have been provided for Figure 1, Figure 1-Figure Supplement 3, Figure 2, Figure 5-Figure Supplement 1, Box 2, Video 1 and Video 2 in the format of microscopy videos. Additionally, representative microscopy videos of all different conditions are provided as a Zenodo dataset (http://doi.org/10.5281/zenodo.3736728). The numerical codes that were used, together with an overview table of the performed experiments, are available through GitHub (Nolet, 2020).
Article and author information
Author details
Felix Eduard Nolet
Funding
Research Foundation - Flanders (GOA5317N)
- Lendert Gelens
KU Leuven Research Fund (C14/18/084)
- Lendert Gelens
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the KU Leuven. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the KU Leuven. The protocol was approved by the Committee on the Ethics of Animal Experiments of the KU Leuven (ECD permit Number: P165/2016 ).
Copyright
© 2020, Nolet et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,981
- views
-
- 367
- downloads
-
- 32
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Nuclei determine the spatial origin of mitotic waves
eLife 9:e52868.
https://doi.org/10.7554/eLife.52868
Further reading
-
- Computational and Systems Biology
Live-cell microscopy routinely provides massive amounts of time-lapse images of complex cellular systems under various physiological or therapeutic conditions. However, this wealth of data remains difficult to interpret in terms of causal effects. Here, we describe CausalXtract, a flexible computational pipeline that discovers causal and possibly time-lagged effects from morphodynamic features and cell–cell interactions in live-cell imaging data. CausalXtract methodology combines network-based and information-based frameworks, which is shown to discover causal effects overlooked by classical Granger and Schreiber causality approaches. We showcase the use of CausalXtract to uncover novel causal effects in a tumor-on-chip cellular ecosystem under therapeutically relevant conditions. In particular, we find that cancer-associated fibroblasts directly inhibit cancer cell apoptosis, independently from anticancer treatment. CausalXtract uncovers also multiple antagonistic effects at different time delays. Hence, CausalXtract provides a unique computational tool to interpret live-cell imaging data for a range of fundamental and translational research applications.
-
- Computational and Systems Biology
- Structural Biology and Molecular Biophysics
Viral adhesion to host cells is a critical step in infection for many viruses, including monkeypox virus (MPXV). In MPXV, the H3 protein mediates viral adhesion through its interaction with heparan sulfate (HS), yet the structural details of this interaction have remained elusive. Using AI-based structural prediction tools and molecular dynamics (MD) simulations, we identified a novel, positively charged α-helical domain in H3 that is essential for HS binding. This conserved domain, found across orthopoxviruses, was experimentally validated and shown to be critical for viral adhesion, making it an ideal target for antiviral drug development. Targeting this domain, we designed a protein inhibitor, which disrupted the H3-HS interaction, inhibited viral infection in vitro and viral replication in vivo, offering a promising antiviral candidate. Our findings reveal a novel therapeutic target of MPXV, demonstrating the potential of combination of AI-driven methods and MD simulations to accelerate antiviral drug discovery.
