PUBLICATION
Modeling the Zebrafish Segmentation Clock's Gene Regulatory Network Constrained by Expression Data Suggests Evolutionary Transitions Between Oscillating and Non-Oscillating Transcription
- Authors
- Schwendinger-Schreck, J., Kang, Y., Holley, S.A.
- ID
- ZDB-PUB-140513-285
- Date
- 2014
- Source
- Genetics 197(2): 725-38 (Journal)
- Registered Authors
- Holley, Scott
- Keywords
- gene regulatory network, her/hes, segmentation clock, simulated annealing, zebrafish
- MeSH Terms
-
- Animals
- Basic Helix-Loop-Helix Transcription Factors/genetics*
- Biological Clocks
- Body Patterning/genetics
- CLOCK Proteins/genetics*
- Computer Simulation
- Gene Expression Regulation, Developmental*
- Gene Knockdown Techniques
- Gene Regulatory Networks*
- Transcription, Genetic
- Zebrafish/embryology
- Zebrafish/genetics*
- Zebrafish Proteins/genetics
- PubMed
- 24663100 Full text @ Genetics
Citation
Schwendinger-Schreck, J., Kang, Y., Holley, S.A. (2014) Modeling the Zebrafish Segmentation Clock's Gene Regulatory Network Constrained by Expression Data Suggests Evolutionary Transitions Between Oscillating and Non-Oscillating Transcription. Genetics. 197(2):725-38.
Abstract
During segmentation of vertebrate embryos, somites form in accordance with a periodic pattern established by the segmentation clock. In the zebrafish (Danio rerio), the segmentation clock includes six hairy/enhancer of split-related (her/hes) genes, five of which oscillate due to negative autofeedback. The non-oscillating gene hes6 forms the hub of a network of ten Her/Hes protein dimers, which includes seven DNA binding dimers and four weak or non-DNA binding dimers. The balance of dimer species is critical for segmentation clock function, and loss of function studies suggest that the her genes have both unique and redundant functions within the clock. However, the precise regulatory interactions underlying the negative feedback loop are unknown. Here, we combine quantitative experimental data, in silico modeling and a global optimization algorithm to identify a gene regulatory network (GRN) designed to fit measured transcriptional responses to gene knockdown. Surprisingly, we find that hes6, the clock gene that does not oscillate, responds to negative feedback. Consistent with prior in silico analyses, we find that variation in transcription, translation, and degradation rates can mediate the gain and loss of oscillatory behavior for genes regulated by negative feedback. Extending our study, we found that transcription of the non-oscillating Fgf pathway gene sef responds to her/hes perturbation similarly to oscillating her genes. These observations suggest a more extensive underlying regulatory similarity between the zebrafish segmentation clock and the mouse and chick segmentation clocks, which exhibit oscillations of her/hes genes as well as numerous other Notch, Fgf and Wnt pathway genes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping