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

  1. Felix Eduard Nolet

    Laboratory of Dynamics in Biological Systems, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9300-6302
  2. Alexandra Vandervelde

    Laboratory of Dynamics in Biological Systems, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  3. Arno Vanderbeke

    Laboratory of Dynamics in Biological Systems, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7240-8377
  4. Liliana Pineros

    Laboratory of Dynamics in Biological Systems, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  5. Jeremy B Chang

    Department of Biosystems, University of California San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Lendert Gelens

    Laboratory of Dynamics in Biological Systems, KU Leuven, Leuven, Belgium
    For correspondence
    lendert.gelens@kuleuven.be
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7290-9561

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.

Reviewing Editor

  1. Stefano Di Talia, Duke University, United States

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
).

Version history

  1. Received: October 18, 2019
  2. Accepted: May 22, 2020
  3. Accepted Manuscript published: May 26, 2020 (version 1)
  4. Version of Record published: June 24, 2020 (version 2)

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

  • 2,851
    views
  • 352
    downloads
  • 27
    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)

  1. Felix Eduard Nolet
  2. Alexandra Vandervelde
  3. Arno Vanderbeke
  4. Liliana Pineros
  5. Jeremy B Chang
  6. Lendert Gelens
(2020)
Nuclei determine the spatial origin of mitotic waves
eLife 9:e52868.
https://doi.org/10.7554/eLife.52868

Share this article

https://doi.org/10.7554/eLife.52868

Further reading

    1. Computational and Systems Biology
    2. Neuroscience
    Andrea I Luppi, Pedro AM Mediano ... Emmanuel A Stamatakis
    Research Article

    How is the information-processing architecture of the human brain organised, and how does its organisation support consciousness? Here, we combine network science and a rigorous information-theoretic notion of synergy to delineate a ‘synergistic global workspace’, comprising gateway regions that gather synergistic information from specialised modules across the human brain. This information is then integrated within the workspace and widely distributed via broadcaster regions. Through functional MRI analysis, we show that gateway regions of the synergistic workspace correspond to the human brain’s default mode network, whereas broadcasters coincide with the executive control network. We find that loss of consciousness due to general anaesthesia or disorders of consciousness corresponds to diminished ability of the synergistic workspace to integrate information, which is restored upon recovery. Thus, loss of consciousness coincides with a breakdown of information integration within the synergistic workspace of the human brain. This work contributes to conceptual and empirical reconciliation between two prominent scientific theories of consciousness, the Global Neuronal Workspace and Integrated Information Theory, while also advancing our understanding of how the human brain supports consciousness through the synergistic integration of information.

    1. Computational and Systems Biology
    2. Genetics and Genomics
    Ardalan Naseri, Degui Zhi, Shaojie Zhang
    Research Article Updated

    Runs-of-homozygosity (ROH) segments, contiguous homozygous regions in a genome were traditionally linked to families and inbred populations. However, a growing literature suggests that ROHs are ubiquitous in outbred populations. Still, most existing genetic studies of ROH in populations are limited to aggregated ROH content across the genome, which does not offer the resolution for mapping causal loci. This limitation is mainly due to a lack of methods for the efficient identification of shared ROH diplotypes. Here, we present a new method, ROH-DICE (runs-of-homozygous diplotype cluster enumerator), to find large ROH diplotype clusters, sufficiently long ROHs shared by a sufficient number of individuals, in large cohorts. ROH-DICE identified over 1 million ROH diplotypes that span over 100 single nucleotide polymorphisms (SNPs) and are shared by more than 100 UK Biobank participants. Moreover, we found significant associations of clustered ROH diplotypes across the genome with various self-reported diseases, with the strongest associations found between the extended human leukocyte antigen (HLA) region and autoimmune disorders. We found an association between a diplotype covering the homeostatic iron regulator (HFE) gene and hemochromatosis, even though the well-known causal SNP was not directly genotyped or imputed. Using a genome-wide scan, we identified a putative association between carriers of an ROH diplotype in chromosome 4 and an increase in mortality among COVID-19 patients (p-value = 1.82 × 10−11). In summary, our ROH-DICE method, by calling out large ROH diplotypes in a large outbred population, enables further population genetics into the demographic history of large populations. More importantly, our method enables a new genome-wide mapping approach for finding disease-causing loci with multi-marker recessive effects at a population scale.