Social and Mathematical Epidemiology Group, London School of Hygiene and Tropical Medicine, Faculty of Public Health and Policy, 15-17 Tavistock Place, London, UK.
J R Soc Interface. 2012 Dec 12;10(79):20120826. doi: 10.1098/rsif.2012.0826. Print 2013 Feb.
The pattern of gene expression in a developing tissue determines the spatial organization of cell type generation. We previously defined regulatory interactions between a set of transcription factors that specify the pattern of gene expression in progenitors of different neuronal subtypes of the vertebrate neural tube. These transcription factors form a circuit that acts as a multistate switch, patterning the tissue in response to a gradient of Sonic Hedgehog. Here, by simplifying aspects of the regulatory interactions, we found that the topology of the circuit allows either switch-like or oscillatory behaviour depending on parameter values. The qualitative dynamics appear to be controlled by a simpler sub-circuit, which we term the AC-DC motif. We argue that its topology provides a natural way to implement a multistate gene expression switch and we show that the circuit is readily extendable to produce more distinct stripes of gene expression. Our analysis also suggests that AC-DC motifs could be deployed in tissues patterned by oscillatory mechanisms, thus blurring the distinction between pattern-formation mechanisms relying on temporal oscillations or graded signals. Furthermore, during evolution, mechanisms of gradient interpretation might have arisen from oscillatory circuits, or vice versa.
在发育组织中基因表达的模式决定了细胞类型生成的空间组织。我们之前定义了一组转录因子之间的调控相互作用，这些转录因子指定了脊椎动物神经管中不同神经元亚型祖细胞中基因表达的模式。这些转录因子形成一个电路，作为一个多稳态开关，响应 Sonic Hedgehog 的梯度来对组织进行模式化。在这里，通过简化调控相互作用的某些方面，我们发现电路的拓扑结构允许开关样或振荡行为，具体取决于参数值。定性动力学似乎由一个更简单的子电路控制，我们称之为 AC-DC 基序。我们认为其拓扑结构为实现多稳态基因表达开关提供了一种自然方式，并且我们表明该电路易于扩展以产生更明显的基因表达条纹。我们的分析还表明，AC-DC 基序可以在由振荡机制模式化的组织中部署，从而模糊了依赖于时间振荡或梯度信号的模式形成机制之间的区别。此外，在进化过程中，梯度解释机制可能源自振荡电路，或者反之亦然。
