Spatial Patterning from an Integrated Wnt/β-catenin and Notch/Delta Gene Circuit.
Spatial Patterning from an Integrated Wnt/β-catenin and Notch/Delta Gene Circuit.
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集成 Wnt/β-连环蛋白和 Notch/Delta 基因电路的空间图案。
DOI：
10.1109/embc.2018.8513462
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Shen,Xiling
中科院分区：
文献类型：
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作者：
Mines,RobertC;Dohlman,Anders;Lim,Sze-Xian;Tung,Kuei-Ling;Wang,Ergang;Shen,Xiling
传统上，Wnt/β-catenin和Notch /Delta信号通路被认为通过不同的机制运作，在组织模式中发挥不同的作用。然而，已有研究表明，b-catenin可以激活Notch /Delta通路中控制其侧抑制机制的信号介质Hesl的转录。为了研究这种非规范串扰机制，我们提出了一种整合这两种途径的新的基因回路，并在双细胞和多细胞环境中进行了模拟。该模型还捕获了Paneth细胞介导的和间质Wnt的产生。仿真验证了基因电路是暂时双稳态的，并且能够在多细胞网格上形成模式。最后，该模型显示了基于Wnt的稳态浓度和b-连环蛋白对Hesl启动子的相对控制量的分支，提供了一种可能的机制来解释为什么在更多样化的干细胞生态位上直接观察到一个均匀的转运扩增细胞群体。
Classically, the Wnt/β-catenin and Notch /Delta signaling pathways were thought to operate through separate mechanisms, performing distinct roles in tissue patterning. However, it has been shown that b-catenin activates transcription of Hesl, a signaling intermediate in the Notch /Delta pathway that controls its lateral inhibition mechanism. To investigate this non-canonical crosstalk mechanism, a new gene circuit, integrating the two pathways, is proposed and simulated in two-cell and multi-cell environments. This model also captures both Paneth cell- mediated and mesenchymal Wnt production. The simulations verify that the gene circuit is temporally bistable and capable of forming a pattern on a multi-cell grid. Last, the model exhibits a bifurcation based on the steady state concentration of Wnt and the relative amount of control b-catenin has over the Hesl promoter, providing a possible mechanism to explain why a homogeneous population of transit amplifying cells is observed directly above the more diverse stem niche.