Computational models of the Notch network elucidate mechanisms of context-dependent signaling.
Computational models of the Notch network elucidate mechanisms of context-dependent signaling.
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DOI：
10.1371/journal.pcbi.1000390
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发表时间：
2009-05
影响因子：
4.3
通讯作者：
Schaffer DV
中科院分区：
文献类型：
--
作者：
Agrawal S;Archer C;Schaffer DV
Notch信号通路通过多种机制控制发育和成年期间的许多细胞命运决定。因此，尽管它在体节发生过程中起着振荡器的作用，但它可以介导全或无细胞命运开关，以影响发育过程中各种组织中的模式形成。此外，虽然在某些情况下需要连续的Notch信号传导，但在其他情况下，瞬时Notch信号足以影响细胞命运决定。然而，这些不同的行为在不同的细胞背景下的信号机制还没有被理解。Notch1沿着两个下游转录因子hes1和RBP-Jk形成了一个复杂的正反馈和负反馈网络，我们已经实施了一个系统生物学方法来计算研究这个基因调控网络。我们的研究结果表明，该系统具有双稳态，并能够切换状态在一个临界水平的Notch信号启动其配体德尔塔在一个特定的参数值范围内。在这种模式下，Delta的瞬时激活也能够诱导Hes1的长时间高表达，根据信号的强度和持续时间模拟"ON"状态。此外，该系统对某些模型参数高度敏感，并且可以通过调谐单个参数值从用作振荡器开关转变为振荡器。这个参数，hes1的转录抑制常数，因此可以定性地控制信号网络的行为。此外，我们发现，该系统能够抑制和减少生物噪声的影响，所产生的随机效应在基因表达的系统，快速响应Notch信号。因此，这项工作有助于我们理解一个重要的细胞命运控制系统，并开始阐明这种背景依赖的信号系统如何在不同的细胞环境中被调节，以表现出完全不同的行为。Notch信号通路是一种进化上保守的信号系统，在生物体发育期间和成年期间参与各种细胞命运决定。虽然相同的核心电路在各种不同的细胞环境中发挥作用，但实验表明它会引起不同的行为和反应。一方面，它作为一个细胞振荡器的关键，为体节发生，而在其他情况下，它可以作为一个细胞命运开关的模式发展组织，例如在果蝇的眼睛。此外，Notch信号传导的故障与各种癌症有关。为了更好地理解使网络在不同环境中发挥独特作用的潜在机制，我们对Notch网络的行为进行了数学建模，包括Notch基因沿着其下游的两个效应转录因子，它们共同形成了一个正反馈环和负反馈环的网络。我们的研究结果表明，系统的定性和定量行为可以很容易地调整的基础上的关键参数，以反映其多重角色。此外，我们的研究结果提供了对导致功能障碍和疾病的信号系统改变的见解，这可用于识别潜在的治疗药物靶点。
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. The Notch signaling pathway is an evolutionarily conserved signaling system that is involved in various cell fate decisions, both during development of an organism and during adulthood. While the same core circuit functions in various different cellular contexts, it has experimentally been shown to elicit varied behaviors and responses. On the one hand, it functions as a cellular oscillator critical for somitogenesis, whereas in other situations, it can function as a cell fate switch to pattern developing tissue, for example in the Drosophila eye. Furthermore, malfunctioning of Notch signaling is implicated in various cancers. To better understand the underlying mechanisms that allow the network to function distinctly in different contexts, we have mathematically modeled the behavior of the Notch network, encompassing the Notch gene along with two of its downstream effector transcription factors, which together form a network of positive and negative feedback loops. Our results indicate that the qualitative and quantitative behavior of the system can readily be tuned based on key parameters to reflect its multiple roles. Furthermore, our results provide insights into alterations in the signaling system that lead to malfunction and hence disease, which could be used to identify potential drug targets for therapy.
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