computational models of the notch network elucidate mechanisms of context-dependent signaling计算模型的等级网络阐明上下文相关的信号机制.pdfVIP

Computational Models of the Notch Network Elucidate Mechanisms of Context-dependent Signaling Smita Agrawal1,2,3¤a, Colin Archer1,2,3¤b, David V. Schaffer1,2,3* 1 Department of Chemical Engineering, University of California Berkeley, Berkeley, California, United States of America, 2 Department of Bioengineering, University of California Berkeley, Berkeley, California, United States of America, 3 Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California, United States of America 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 tran