A balance of positive and negative regulators determines the pace of the segmentation clock
- University of Dundee, United Kingdom
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
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
-
- 2,324
- views
-
- 503
- 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)
A balance of positive and negative regulators determines the pace of the segmentation clock
eLife 4:e05842.
https://doi.org/10.7554/eLife.05842
