1. Computational and Systems Biology
  2. Developmental Biology
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A balance of positive and negative regulators determines the pace of the segmentation clock

Research Article
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Cite this article as: eLife 2015;4:e05842 doi: 10.7554/eLife.05842

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.

Reviewing Editor

  1. Janet Rossant, University of Toronto, Canada

Publication history

  1. Received: December 8, 2014
  2. Accepted: September 2, 2015
  3. Accepted Manuscript published: September 10, 2015 (version 1)
  4. Version of Record published: October 13, 2015 (version 2)

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.

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