--- _id: '4531' abstract: - lang: eng text: Caenorhabditis elegans vulval development provides an important paradigm for studying the process of cell fate determination and pattern formation during animal development. Although many genes controlling vulval cell fate specification have been identified, how they orchestrate themselves to generate a robust and invariant pattern of cell fates is not yet completely understood. Here, we have developed a dynamic computational model incorporating the current mechanistic understanding of gene interactions during this patterning process. A key feature of our model is the inclusion of multiple modes of crosstalk between the epidermal growth factor receptor (EGFR) and LIN-12/Notch signaling pathways, which together determine the fates of the six vulval precursor cells (VPCs). Computational analysis, using the model-checking technique, provides new biological insights into the regulatory network governing VPC fate specification and predicts novel negative feedback loops. In addition, our analysis shows that most mutations affecting vulval development lead to stable fate patterns in spite of variations in synchronicity between VPCs. Computational searches for the basis of this robustness show that a sequential activation of the EGFR-mediated inductive signaling and LIN-12 / Notch-mediated lateral signaling pathways is key to achieve a stable cell fate pattern. We demonstrate experimentally a time-delay between the activation of the inductive and lateral signaling pathways in wild-type animals and the loss of sequential signaling in mutants showing unstable fate patterns; thus, validating two key predictions provided by our modeling work. The insights gained by our modeling study further substantiate the usefulness of executing and analyzing mechanistic models to investigate complex biological behaviors. acknowledgement: This work was supported in part by the Swiss National Science Foundation (grant 205321–111840). author: - first_name: Jasmin full_name: Fisher, Jasmin last_name: Fisher - first_name: Nir full_name: Piterman, Nir last_name: Piterman - first_name: Alex full_name: Hajnal, Alex last_name: Hajnal - first_name: Thomas A full_name: Thomas Henzinger id: 40876CD8-F248-11E8-B48F-1D18A9856A87 last_name: Henzinger orcid: 0000−0002−2985−7724 citation: ama: Fisher J, Piterman N, Hajnal A, Henzinger TA. Predictive modeling of signaling crosstalk during C. elegans vulval development. PLoS Computational Biology. 2007;3(5):e92. doi:10.1371/journal.pcbi.0030092 apa: Fisher, J., Piterman, N., Hajnal, A., & Henzinger, T. A. (2007). Predictive modeling of signaling crosstalk during C. elegans vulval development. PLoS Computational Biology. Public Library of Science. https://doi.org/10.1371/journal.pcbi.0030092 chicago: Fisher, Jasmin, Nir Piterman, Alex Hajnal, and Thomas A Henzinger. “Predictive Modeling of Signaling Crosstalk during C. Elegans Vulval Development.” PLoS Computational Biology. Public Library of Science, 2007. https://doi.org/10.1371/journal.pcbi.0030092. ieee: J. Fisher, N. Piterman, A. Hajnal, and T. A. Henzinger, “Predictive modeling of signaling crosstalk during C. elegans vulval development,” PLoS Computational Biology, vol. 3(5):e92. Public Library of Science, 2007. ista: Fisher J, Piterman N, Hajnal A, Henzinger TA. 2007. Predictive modeling of signaling crosstalk during C. elegans vulval development. PLoS Computational Biology. 3(5):e92. mla: Fisher, Jasmin, et al. “Predictive Modeling of Signaling Crosstalk during C. Elegans Vulval Development.” PLoS Computational Biology, vol. 3(5):e92, Public Library of Science, 2007, doi:10.1371/journal.pcbi.0030092. short: J. Fisher, N. Piterman, A. Hajnal, T.A. Henzinger, PLoS Computational Biology 3(5):e92 (2007). date_created: 2018-12-11T12:09:20Z date_published: 2007-05-18T00:00:00Z date_updated: 2021-01-12T07:59:29Z day: '18' doi: 10.1371/journal.pcbi.0030092 extern: 1 month: '05' publication: PLoS Computational Biology publication_status: published publisher: Public Library of Science publist_id: '195' quality_controlled: 0 status: public title: Predictive modeling of signaling crosstalk during C. elegans vulval development tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article volume: 3(5):e92 year: '2007' ...