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.
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.
- Janet Rossant, University of Toronto, Canada
© 2015, Wiedermann et al.
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