Genetic robustness is an important characteristic to tolerate genetic or nongenetic perturbations and ensure phenotypic stability. Morphogens, a type of evolutionarily conserved diffusible molecules, govern tissue patterns in a direction-dependent or concentration-dependent manner by differentially regulating downstream gene expression. However, whether the morphogen-directed gene regulatory network possesses genetic robustness remains elusive. In the present study, we collected 4217 morphogen-responsive genes along A-P axis of Drosophila wing discs from the RNA-seq data, and clustered them into 12 modules. By applying mathematical model to the measured data, we constructed a gene modular network (GMN) to decipher the module regulatory interactions and robustness in morphogen-directed development. The computational analyses on asymptotical dynamics of this GMN demonstrated that this morphogen-directed GMN is robust to tolerate a majority of genetic perturbations, which has been further validated by biological experiments. Furthermore, besides the genetic alterations, we further demonstrated that this morphogen-directed GMN can well tolerate nongenetic perturbations (Hh production changes) via computational analyses and experimental validation. Therefore, these findings clearly indicate that the morphogen-directed GMN is robust in response to perturbations and is important for Drosophila to ensure the proper tissue patterning in wing disc.

遗传稳健性是耐受遗传或非遗传扰动并确保表型稳定性的重要特征。形态发生素是一类进化上保守的可扩散分子，通过差异调节下游基因表达，以方向依赖或浓度依赖的方式控制组织模式。然而，形态发生素指导的基因调控网络是否具有遗传鲁棒性仍然是个未知数。在本研究中，我们从RNA-seq数据中收集了沿着果蝇翼盘AP轴的4217个形态发生素响应基因，并将它们聚类成12个模块。通过将数学模型应用于测量数据，我们构建了基因模块化网络（GMN）来破译模块调控相互作用和形态素导向发育中的鲁棒性。对该 GMN 渐近动力学的计算分析表明，这种形态素导向的 GMN 具有鲁棒性，能够耐受大多数遗传扰动，这已通过生物实验得到进一步验证。此外，除了遗传改变之外，我们还通过计算分析和实验验证进一步证明了这种形态发生素导向的 GMN 可以很好地耐受非遗传扰动（Hh 产生变化）。因此，这些发现清楚地表明，形态发生素导向的 GMN 对扰动的反应是稳健的，对于果蝇确保翼盘中正确的组织模式非常重要。