Short-lived Her proteins drive robust synchronized oscillations in the zebrafish segmentation clock
- Authors
- Ay, A., Knierer, S., Sperlea, A., Holland, J., and Ozbudak, E.M.
- ID
- ZDB-PUB-130726-16
- Date
- 2013
- Source
- Development (Cambridge, England) 140(15): 3244-3253 (Journal)
- Registered Authors
- Knierer, Stephan, Ozbudak, Ertugrul
- Keywords
- segmentation clock, oscillation, protein half-life, systems biology, computational modeling, zebrafish
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Basic Helix-Loop-Helix Transcription Factors/genetics
- Basic Helix-Loop-Helix Transcription Factors/physiology
- Biological Clocks/genetics
- Biological Clocks/physiology*
- Body Patterning/genetics
- Body Patterning/physiology*
- Gene Expression Regulation, Developmental
- Gene Knockout Techniques
- Half-Life
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/physiology
- Membrane Proteins/genetics
- Membrane Proteins/physiology
- Models, Biological
- Mutation
- Receptors, Notch/physiology
- Somites/embryology
- Stochastic Processes
- Transcription Factors/genetics
- Transcription Factors/physiology*
- Zebrafish/embryology*
- Zebrafish/genetics
- Zebrafish/physiology*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/physiology*
- PubMed
- 23861061 Full text @ Development
Oscillations are prevalent in natural systems. A gene expression oscillator, called the segmentation clock, controls segmentation of precursors of the vertebral column. Genes belonging to the Hes/her family encode the only conserved oscillating genes in all analyzed vertebrate species. Hes/Her proteins form dimers and negatively autoregulate their own transcription. Here, we developed a stochastic two-dimensional multicellular computational model to elucidate how the dynamics, i.e. period, amplitude and synchronization, of the segmentation clock are regulated. We performed parameter searches to demonstrate that autoregulatory negative-feedback loops of the redundant repressor Her dimers can generate synchronized gene expression oscillations in wild-type embryos and reproduce the dynamics of the segmentation oscillator in different mutant conditions. Our model also predicts that synchronized oscillations can be robustly generated as long as the half-lives of the repressor dimers are shorter than 6 minutes. We validated this prediction by measuring, for the first time, the half-life of Her7 protein as 3.5 minutes. These results demonstrate the importance of building biologically realistic stochastic models to test biological models more stringently and make predictions for future experimental studies.