Neural Differentiation Dynamics Controlled by Multiple Feedback Loops in a Comprehensive Molecular Interaction Network
by
Tsuyoshi Iwasaki 1,2, Ryo Takiguchi 2, Takumi Hiraiwa 2, Takahiro G. Yamada 2, Kazuto Yamazaki 1, Noriko F. Hiroi 2,3,* and Akira Funahashi 2
Tsuyoshi Iwasaki 1,2, Ryo Takiguchi 2, Takumi Hiraiwa 2, Takahiro G. Yamada 2, Kazuto Yamazaki 1, Noriko F. Hiroi 2,3,* and Akira Funahashi 2
1
Research Division, Sumitomo Dainippon Pharma. Co. Ltd, Osaka 554-0022, Japan
2
Department of Biosciences and Informatics, Keio University, Yokohama 223-8522, Japan
3
Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Yamaguchi 756-0884, Japan
*
Author to whom correspondence should be addressed.
Processes 2020, 8(2), 166; https://doi.org/10.3390/pr8020166
Received: 23 December 2019 / Revised: 24 January 2020 / Accepted: 26 January 2020 / Published: 2 February 2020
(This article belongs to the Section Biological Systems)
Mathematical model simulation is a useful method for understanding the complex behavior of a living system. The construction of mathematical models using comprehensive information is one of the techniques of model construction. Such a comprehensive knowledge-based network tends to become a large-scale network. As a result, the variation of analyses is limited to a particular kind of analysis because of the size and complexity of the model. To analyze a large-scale regulatory network of neural differentiation, we propose a contractive method that preserves the dynamic behavior of a large network. The method consists of the following two steps: comprehensive network building and network reduction. The reduction phase can extract network loop structures from a large-scale regulatory network, and the subnetworks were combined to preserve the dynamics of the original large-scale network. We confirmed that the extracted loop combination reproduced the known dynamics of HES1 and ASCL1 before and after differentiation, including oscillation and equilibrium of their concentrations. The model also reproduced the effects of the overexpression and knockdown of the Id2 gene. Our model suggests that the characteristic change in HES1 and ASCL1 expression in the large-scale regulatory network is controlled by a combination of four feedback loops, including a large loop, which has not been focused on. The model extracted by our method has the potential to reveal the critical mechanisms of neural differentiation. The method is applicable to other biological events.
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Iwasaki, T.; Takiguchi, R.; Hiraiwa, T.; Yamada, T.G.; Yamazaki, K.; Hiroi, N.F.; Funahashi, A. Neural Differentiation Dynamics Controlled by Multiple Feedback Loops in a Comprehensive Molecular Interaction Network. Processes 2020, 8, 166.
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