Institute of Systems Biology, Shanghai University, Shanghai 200444, China.
Bioinformatics. 2011 Nov 15;27(22):3158-65. doi: 10.1093/bioinformatics/btr551. Epub 2011 Oct 11.
In the developing nervous system, the expression of proneural genes, i.e. Hes1, Neurogenin-2 (Ngn2) and Deltalike-1 (Dll1), oscillates in neural progenitors with a period of 2-3 h, but is persistent in post-mitotic neurons. Unlike the synchronization of segmentation clocks, oscillations in neural progenitors are asynchronous between cells. It is known that Notch signaling, in which Notch in a cell can be activated by Dll1 in neighboring cells (trans-activation) and can also be inhibited by Dll1 within the same cell (cis-inhibition), is important for neural fate decisions. There have been extensive studies of trans-activation, but the operating mechanisms and potential implications of cis-inhibition are less clear and need to be further investigated.
In this article, we present a computational model for neural fate decisions based on intertwined dynamics with trans-activation and cis-inhibition involving the Hes1, Notch and Dll1 proteins. In agreement with experimental observations, the model predicts that both trans-activation and cis-inhibition play critical roles in regulating the choice between remaining as a progenitor and embarking on neural differentiation. In particular, trans-activation is essential for generation of oscillations in neural progenitors, and cis-inhibition is important for the asynchrony between adjacent cells, indicating that the asynchronous oscillations in neural progenitors depend on cooperation between trans-activation and cis-inhibition. In contrast, cis-inhibition plays more critical roles in embarking on neural differentiation by inactivating intercellular Notch signaling. The model presented here might be a good candidate for providing the first qualitative mechanism of neural fate decisions mediated by both trans-activation and cis-inhibition.
在发育中的神经系统中，神经前体细胞基因（如 Hes1、Neurogenin-2（Ngn2）和 Delta-like-1（Dll1））的表达呈 2-3 小时的周期振荡，但在有丝分裂后的神经元中持续存在。与分段时钟的同步不同，神经前体细胞中的振荡在细胞之间是异步的。众所周知，Notch 信号通路在其中一个细胞中的 Notch 可以被相邻细胞中的 Dll1 激活（转激活），也可以被同一细胞内的 Dll1 抑制（顺式抑制），对于神经命运决定很重要。已经对转激活进行了广泛的研究，但顺式抑制的作用机制和潜在影响不太清楚，需要进一步研究。
在本文中，我们提出了一个基于涉及 Hes1、Notch 和 Dll1 蛋白的转激活和顺式抑制的交织动力学的神经命运决定的计算模型。与实验观察一致，该模型预测转激活和顺式抑制都在调节保持作为祖细胞和开始神经分化之间的选择中发挥关键作用。特别是，转激活对于神经前体细胞中振荡的产生是必不可少的，而顺式抑制对于相邻细胞之间的异步性很重要，表明神经前体细胞中的异步振荡依赖于转激活和顺式抑制之间的合作。相比之下，顺式抑制通过使细胞间 Notch 信号失活，在开始神经分化中发挥更关键的作用。本文提出的模型可能是提供由转激活和顺式抑制介导的神经命运决定的第一个定性机制的良好候选者。
