Computational models of the Notch network elucidate mechanisms of context-dependent signaling

Agrawal, Smita, Archer, Colin and Schaffer, David V. (2009) Computational models of the Notch network elucidate mechanisms of context-dependent signaling. PLoS Computational Biology, 5 5: . doi:10.1371/journal.pcbi.1000390

Author Agrawal, Smita
Archer, Colin
Schaffer, David V.
Title Computational models of the Notch network elucidate mechanisms of context-dependent signaling
Journal name PLoS Computational Biology   Check publisher's open access policy
ISSN 1553-734X
Publication date 2009-05-01
Sub-type Article (original research)
DOI 10.1371/journal.pcbi.1000390
Open Access Status DOI
Volume 5
Issue 5
Total pages 14
Place of publication San Francisco, United States
Publisher Public Library of Science
Language eng
Formatted abstract
The Notch signaling pathway controls numerous cell fate decisions during development and adulthood through diverse mechanisms. Thus, whereas it functions as an oscillator during somitogenesis, it can mediate an all-or-none cell fate switch to influence pattern formation in various tissues during development. Furthermore, while in some contexts continuous Notch signaling is required, in others a transient Notch signal is sufficient to influence cell fate decisions. However, the signaling mechanisms that underlie these diverse behaviors in different cellular contexts have not been understood. Notch1 along with two downstream transcription factors hes1 and RBP-Jk forms an intricate network of positive and negative feedback loops, and we have implemented a systems biology approach to computationally study this gene regulation network. Our results indicate that the system exhibits bistability and is capable of switching states at a critical level of Notch signaling initiated by its ligand Delta in a particular range of parameter values. In this mode, transient activation of Delta is also capable of inducing prolonged high expression of Hes1, mimicking the “ON” state depending on the intensity and duration of the signal. Furthermore, this system is highly sensitive to certain model parameters and can transition from functioning as a bistable switch to an oscillator by tuning a single parameter value. This parameter, the transcriptional repression constant of hes1, can thus qualitatively govern the behavior of the signaling network. In addition, we find that the system is able to dampen and reduce the effects of biological noise that arise from stochastic effects in gene expression for systems that respond quickly to Notch signaling.

This work thus helps our understanding of an important cell fate control system and begins to elucidate how this context dependent signaling system can be modulated in different cellular settings to exhibit entirely different behaviors.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ
Additional Notes Article number e1000390

Document type: Journal Article
Sub-type: Article (original research)
Collection: Australian Institute for Bioengineering and Nanotechnology Publications
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Citation counts: TR Web of Science Citation Count  Cited 44 times in Thomson Reuters Web of Science Article | Citations
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