Abstract

Somitogenesis is regulated by a molecular oscillator which drives dynamic gene expression within the PSM with a periodicity tightly coupled to somite formation. Previous mathematical models that invoke the mechanism of delayed negative feedback predict the oscillation period depends on the sum of delays in negative-feedback loops and the inhibitor half-lives. We develop a model to explore the possibility positive feedback also plays a role. The model predicts increasing the half-life of the positive regulator, Notch intracellular domain (NICD), can lead to elevated NICD levels and an increase in the oscillation period. To test this, we investigate a phenotype induced by various small molecule inhibitors in which the clock is slowed. We observe elevated levels and prolonged half-life of NICD. Reducing NICD production rescues these effects. These data provide the first indication tight control of the turnover of positive as well as negative regulators of the clock determines its periodicity.

Article and author information

Author details

  1. Guy Wiedermann

    Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Robert Alexander Bone

    Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Joana Clara Silva

    Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Mia Bjorklund

    Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Philip Murray

    Division of Mathematics, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. J Kim Dale

    Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee, United Kingdom
    For correspondence
    j.k.dale@dundee.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed under a home office license issued to Dr Kim Dale and under the regulations of the home office Animal Welfare ACT. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the University of Dundee. The protocol was approved by the ethical committee of the University of Dundee. Every effort was made to minimize suffering.

Copyright

© 2015, Wiedermann 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

  • 2,312
    views
  • 497
    downloads
  • 26
    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. Guy Wiedermann
  2. Robert Alexander Bone
  3. Joana Clara Silva
  4. Mia Bjorklund
  5. Philip Murray
  6. J Kim Dale
(2015)
A balance of positive and negative regulators determines the pace of the segmentation clock
eLife 4:e05842.
https://doi.org/10.7554/eLife.05842

Share this article

https://doi.org/10.7554/eLife.05842

Further reading

    1. Cancer Biology
    2. Computational and Systems Biology
    Nayoung Kim, Sehhoon Park ... Myung-Ju Ahn
    Research Article

    This study investigates the variability among patients with non-small cell lung cancer (NSCLC) in their responses to immune checkpoint inhibitors (ICIs). Recognizing that patients with advanced-stage NSCLC rarely qualify for surgical interventions, it becomes crucial to identify biomarkers that influence responses to ICI therapy. We conducted an analysis of single-cell transcriptomes from 33 lung cancer biopsy samples, with a particular focus on 14 core samples taken before the initiation of palliative ICI treatment. Our objective was to link tumor and immune cell profiles with patient responses to ICI. We discovered that ICI non-responders exhibited a higher presence of CD4+ regulatory T cells, resident memory T cells, and TH17 cells. This contrasts with the diverse activated CD8+ T cells found in responders. Furthermore, tumor cells in non-responders frequently showed heightened transcriptional activity in the NF-kB and STAT3 pathways, suggesting a potential inherent resistance to ICI therapy. Through the integration of immune cell profiles and tumor molecular signatures, we achieved an discriminative power (area under the curve [AUC]) exceeding 95% in identifying patient responses to ICI treatment. These results underscore the crucial importance of the interplay between tumor and immune microenvironment, including within metastatic sites, in affecting the effectiveness of ICIs in NSCLC.

    1. Computational and Systems Biology
    2. Developmental Biology
    Rosalio Reyes, Arthur D Lander, Marcos Nahmad
    Research Article

    Understanding the principles underlying the design of robust, yet flexible patterning systems is a key problem in developmental biology. In the Drosophila wing, Hedgehog (Hh) signaling determines patterning outputs using dynamical properties of the Hh gradient. In particular, the pattern of collier (col) is established by the steady-state Hh gradient, whereas the pattern of decapentaplegic (dpp), is established by a transient gradient of Hh known as the Hh overshoot. Here we use mathematical modeling to suggest that this dynamical interpretation of the Hh gradient results in specific robustness and precision properties. For instance, the location of the anterior border of col, which is subject to self-enhanced ligand degradation is more robustly specified than that of dpp to changes in morphogen dosage, and we provide experimental evidence of this prediction. However, the anterior border of dpp expression pattern, which is established by the overshoot gradient is much more precise to what would be expected by the steady-state gradient. Therefore, the dynamical interpretation of Hh signaling offers tradeoffs between