title: Short-lived Her proteins drive robust synchronized oscillations in the zebrafish segmentation clock.
abstract: 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.
authors.affiliation: Department of Mathematics, Colgate University, Hamilton, NY 13346, USA.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Ay
authors.forename: Stephan
authors.initials: S
authors.lastname: Knierer
authors.forename: Adriana
authors.initials: A
authors.lastname: Sperlea
authors.forename: Jack
authors.initials: J
authors.lastname: Holland
authors.forename: Ertuğrul M
authors.initials: EM
authors.lastname: Özbudak
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology; D001683:Biological Clocks / Q000235:genetics / Q000502:physiology*; D019521:Body Patterning / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D006207:Half-Life; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D008954:Models, Biological; D009154:Mutation; D051880:Receptors, Notch / Q000502:physiology; D019170:Somites / Q000196:embryology; D013269:Stochastic Processes; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D014157:Transcription Factors; D029961:Zebrafish Proteins; C460099:HER7 protein, zebrafish; C064045:delta protein; C491619:her1 protein, zebrafish
keywords: Computational modeling; Oscillation; Protein half-life; Segmentation clock; Systems biology; Zebrafish