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Predictive modeling of signaling crosstalk during C. elegans vulval development


Fisher, J; Piterman, N; Hajnal, A; Henzinger, T A (2007). Predictive modeling of signaling crosstalk during C. elegans vulval development. PLoS Computational Biology, 3(5):e92.

Abstract

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
Uncontrolled Keywords:C. elegans, EGFR, computational modeling, LIN-12
Language:English
Date:18 May 2007
Deposited On:11 Feb 2008 12:14
Last Modified:01 Sep 2016 07:05
Publisher:Public Library of Science (PLoS)
ISSN:1553-734X
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1371/journal.pcbi.0030092
PubMed ID:17511512
Permanent URL: http://doi.org/10.5167/uzh-262

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