Verd Berta, Crombach Anton, Jaeger Johannes
EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
PLoS Comput Biol. 2017 Feb 3;13(2):e1005285. doi: 10.1371/journal.pcbi.1005285. eCollection 2017 Feb.
Pattern formation during development is a highly dynamic process. In spite of this, few experimental and modelling approaches take into account the explicit time-dependence of the rules governing regulatory systems. We address this problem by studying dynamic morphogen interpretation by the gap gene network in Drosophila melanogaster. Gap genes are involved in segment determination during early embryogenesis. They are activated by maternal morphogen gradients encoded by bicoid (bcd) and caudal (cad). These gradients decay at the same time-scale as the establishment of the antero-posterior gap gene pattern. We use a reverse-engineering approach, based on data-driven regulatory models called gene circuits, to isolate and characterise the explicitly time-dependent effects of changing morphogen concentrations on gap gene regulation. To achieve this, we simulate the system in the presence and absence of dynamic gradient decay. Comparison between these simulations reveals that maternal morphogen decay controls the timing and limits the rate of gap gene expression. In the anterior of the embyro, it affects peak expression and leads to the establishment of smooth spatial boundaries between gap domains. In the posterior of the embryo, it causes a progressive slow-down in the rate of gap domain shifts, which is necessary to correctly position domain boundaries and to stabilise the spatial gap gene expression pattern. We use a newly developed method for the analysis of transient dynamics in non-autonomous (time-variable) systems to understand the regulatory causes of these effects. By providing a rigorous mechanistic explanation for the role of maternal gradient decay in gap gene regulation, our study demonstrates that such analyses are feasible and reveal important aspects of dynamic gene regulation which would have been missed by a traditional steady-state approach. More generally, it highlights the importance of transient dynamics for understanding complex regulatory processes in development.
发育过程中的模式形成是一个高度动态的过程。尽管如此，很少有实验和建模方法考虑到调控系统规则的明确时间依赖性。我们通过研究黑腹果蝇中缺口基因网络对动态形态发生素的解读来解决这个问题。缺口基因参与早期胚胎发育过程中的体节确定。它们由双胸蛋白（bcd）和尾蛋白（cad）编码的母体形态发生素梯度激活。这些梯度在前后缺口基因模式建立的相同时间尺度上衰减。我们使用一种基于称为基因回路的数据驱动调控模型的逆向工程方法，来分离和表征形态发生素浓度变化对缺口基因调控的明确时间依赖性影响。为了实现这一点，我们在存在和不存在动态梯度衰减的情况下模拟该系统。这些模拟之间的比较表明，母体形态发生素衰减控制着缺口基因表达的时间并限制其速率。在胚胎前部，它影响峰值表达并导致缺口结构域之间形成平滑的空间边界。在胚胎后部，它导致缺口结构域移动速率逐渐减慢，这对于正确定位结构域边界和稳定空间缺口基因表达模式是必要的。我们使用一种新开发的方法来分析非自治（时变）系统中的瞬态动力学，以理解这些效应的调控原因。通过为母体梯度衰减在缺口基因调控中的作用提供严格的机制解释，我们的研究表明这种分析是可行的，并揭示了动态基因调控的重要方面，而这些方面是传统稳态方法所遗漏的。更普遍地说，它强调了瞬态动力学对于理解发育中复杂调控过程的重要性。
