Mines Robert C, Dohlman Anders, Lim Sze-Xian, Tung Kuei-Ling, Wang Ergang, Shen Xiling
Annu Int Conf IEEE Eng Med Biol Soc. 2018 Jul;2018:5022-5025. doi: 10.1109/EMBC.2018.8513462.
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.
传统上，Wnt/β-连环蛋白和Notch/Delta信号通路被认为通过不同的机制发挥作用，在组织模式形成中扮演不同的角色。然而，研究表明β-连环蛋白可激活Hesl的转录，Hesl是Notch/Delta信号通路中的一个信号中间体，控制其侧向抑制机制。为了研究这种非经典的串扰机制，我们提出了一个整合这两条信号通路的新基因回路，并在双细胞和多细胞环境中进行了模拟。该模型还捕捉到了潘氏细胞介导的和间充质Wnt的产生。模拟结果验证了该基因回路在时间上是双稳态的，并且能够在多细胞网格上形成一种模式。最后，该模型基于Wnt的稳态浓度以及β-连环蛋白对Hesl启动子的控制相对量表现出一种分岔现象，为解释为什么在更多样化的干细胞龛上方直接观察到均一的过渡放大细胞群体提供了一种可能的机制。
