---
_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'
...