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Topology and dynamics of the zebrafish segmentation clock core circuit.

Schröter, C; Ares, S; Morelli, LG; Isakova, A; Hens, K; Soroldoni, D; Gajewski, M; ... Oates, AC; + view all (2012) Topology and dynamics of the zebrafish segmentation clock core circuit. PLoS Biology , 10 (7) , Article e1001364. 10.1371/journal.pbio.1001364. Green open access

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Abstract

During vertebrate embryogenesis, the rhythmic and sequential segmentation of the body axis is regulated by an oscillating genetic network termed the segmentation clock. We describe a new dynamic model for the core pace-making circuit of the zebrafish segmentation clock based on a systematic biochemical investigation of the network's topology and precise measurements of somitogenesis dynamics in novel genetic mutants. We show that the core pace-making circuit consists of two distinct negative feedback loops, one with Her1 homodimers and the other with Her7:Hes6 heterodimers, operating in parallel. To explain the observed single and double mutant phenotypes of her1, her7, and hes6 mutant embryos in our dynamic model, we postulate that the availability and effective stability of the dimers with DNA binding activity is controlled in a "dimer cloud" that contains all possible dimeric combinations between the three factors. This feature of our model predicts that Hes6 protein levels should oscillate despite constant hes6 mRNA production, which we confirm experimentally using novel Hes6 antibodies. The control of the circuit's dynamics by a population of dimers with and without DNA binding activity is a new principle for the segmentation clock and may be relevant to other biological clocks and transcriptional regulatory networks.

Type: Article
Title: Topology and dynamics of the zebrafish segmentation clock core circuit.
Location: US
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pbio.1001364
Publisher version: http://dx.doi.org/10.1371/journal.pbio.1001364
Language: English
Additional information: © 2012 Schröter et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMCID: PMC3404119
Keywords: Animals, Basic Helix-Loop-Helix Transcription Factors, Biological Clocks, Body Patterning, Dimerization, Feedback, Physiological, Gene Expression Regulation, Developmental, Models, Biological, Phenotype, Promoter Regions, Genetic, Protein Interaction Mapping, Protein Interaction Maps, Protein Stability, RNA, Messenger, Repressor Proteins, Somites, Substrate Specificity, Transcription Factors, Transcription, Genetic, Two-Hybrid System Techniques, Zebrafish, Zebrafish Proteins
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: https://discovery.ucl.ac.uk/id/eprint/1373228
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