Modeling Wnt/β-Catenin Target Gene Expression in APC and Wnt Gradients Under Wild Type and Mutant Conditions.
Modeling Wnt/β-Catenin Target Gene Expression in APC and Wnt Gradients Under Wild Type and Mutant Conditions.
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DOI：
10.3389/fphys.2013.00021
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发表时间：
2013
影响因子：
4
通讯作者：
Wolf J
中科院分区：
文献类型：
--
作者：
Benary U;Kofahl B;Hecht A;Wolf J
Wnt/β - 连环蛋白通路通过控制靶基因的差异表达参与多种生理过程的调节。在某些组织中，比如成年肝脏，由于Wnt配体和/或诸如APC等细胞内通路组分的梯度，Wnt/β - 连环蛋白通路能够达到不同水平的活性。分级的通路活性如何转化为Wnt/β - 连环蛋白靶基因表达的区域特异性模式在很大程度上是未知的。在此，我们应用一种数学建模方法来研究不同调节机制对Wnt或APC浓度梯度内靶基因表达的影响。我们开发了一个Wnt/β - 连环蛋白信号转导的最简模型，并将其与各种靶基因调节机制相结合。特别是，比较了激活、抑制以及非相干前馈回路（iFFL）的作用。为了明确激活动力学，我们分析了量化β - 连环蛋白/TCF报告基因构建体对不同Wnt浓度响应的实验数据，并证明这些构建体的诱导以一种协同方式发生，希尔系数在2到5之间。总之，我们的研究表明，特定基因调节机制与不依赖时间的Wnt或APC梯度相结合，足以产生在肝脏中已通过实验观察到的独特靶基因表达模式。我们发现，协同基因激活与TCF反馈相结合能够在Wnt或APC梯度中建立靶基因表达的清晰边界。相反，iFFL使基因表达不受上游信号组分梯度的影响。我们随后对致癌通路突变的分析表明，它们对基因表达的影响由基因调节机制以及突变发生所在细胞的APC浓度所决定。
The Wnt/β-catenin pathway is involved in the regulation of a multitude of physiological processes by controlling the differential expression of target genes. In certain tissues such as the adult liver, the Wnt/β-catenin pathway can attain different levels of activity due to gradients of Wnt ligands and/or intracellular pathway components like APC. How graded pathway activity is converted into regionally distinct patterns of Wnt/β-catenin target gene expression is largely unknown. Here, we apply a mathematical modeling approach to investigate the impact of different regulatory mechanisms on target gene expression within Wnt or APC concentration gradients. We develop a minimal model of Wnt/β-catenin signal transduction and combine it with various mechanisms of target gene regulation. In particular, the effects of activation, inhibition, and an incoherent feedforward loop (iFFL) are compared. To specify activation kinetics, we analyze experimental data that quantify the response of β-catenin/TCF reporter constructs to different Wnt concentrations, and demonstrate that the induction of these constructs occurs in a cooperative manner with Hill coefficients between 2 and 5. In summary, our study shows that the combination of specific gene regulatory mechanisms with a time-independent gradient of Wnt or APC is sufficient to generate distinct target gene expression patterns as have been experimentally observed in liver. We find that cooperative gene activation in combination with a TCF feedback can establish sharp borders of target gene expression in Wnt or APC gradients. In contrast, the iFFL renders gene expression independent of gradients of the upstream signaling components. Our subsequent analysis of carcinogenic pathway mutations reveals that their impact on gene expression is determined by the gene regulatory mechanism and the APC concentration of the cell in which the mutation occurs.
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