title: Spatial gradients of protein-level time delays set the pace of the traveling segmentation clock waves.
abstract: The vertebrate segmentation clock is a gene expression oscillator controlling rhythmic segmentation of the vertebral column during embryonic development. The period of oscillations becomes longer as cells are displaced along the posterior to anterior axis, which results in traveling waves of clock gene expression sweeping in the unsegmented tissue. Although various hypotheses necessitating the inclusion of additional regulatory genes into the core clock network at different spatial locations have been proposed, the mechanism underlying traveling waves has remained elusive. Here, we combined molecular-level computational modeling and quantitative experimentation to solve this puzzle. Our model predicts the existence of an increasing gradient of gene expression time delays along the posterior to anterior direction to recapitulate spatiotemporal profiles of the traveling segmentation clock waves in different genetic backgrounds in zebrafish. We validated this prediction by measuring an increased time delay of oscillatory Her1 protein production along the unsegmented tissue. Our results refuted the need for spatial expansion of the core feedback loop to explain the occurrence of traveling waves. Spatial regulation of gene expression time delays is a novel way of creating dynamic patterns; this is the first report demonstrating such a control mechanism in any tissue and future investigations will explore the presence of analogous examples in other biological systems.
authors.affiliation: Department of Mathematics, Colgate University, Hamilton, NY 13346, USA Department of Biology, Colgate University, Hamilton, NY 13346, USA aay@colgate.edu ertugrul.ozbudak@einstein.yu.edu.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Ay
authors.affiliation: Department of Computer Science, Colgate University, Hamilton, NY 13346, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Holland
authors.affiliation: Department of Computer Science, Colgate University, Hamilton, NY 13346, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Sperlea
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Gnanapackiam Sheela
authors.initials: GS
authors.lastname: Devakanmalai
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Knierer
authors.affiliation: Department of Mathematics, Colgate University, Hamilton, NY 13346, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Sangervasi
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Angel
authors.initials: A
authors.lastname: Stevenson
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA aay@colgate.edu ertugrul.ozbudak@einstein.yu.edu.
authors.forename: Ertuğrul M
authors.initials: EM
authors.lastname: Ozbudak
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D019170:Somites / Q000196:embryology / Q000378:metabolism; D049490:Systems Biology; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029961:Zebrafish Proteins
keywords: Computational modeling; Gene expression; Oscillation; Segmentation clock; Systems biology; Traveling wave