During embryonic development, signalling pathways orchestrate organogenesis by controlling tissue-specific gene expression programmes and differentiation. Although the molecular components of many common developmental signalling systems are known, our current understanding of how signalling inputs are translated into gene expression outputs in real-time is limited. Here we employ optogenetics to control the activation of Notch signalling during Drosophila embryogenesis with minute accuracy and follow target gene expression by quantitative live imaging. Light-induced nuclear translocation of the Notch Intracellular Domain (NICD) causes a rapid activation of target mRNA expression. However, target gene transcription gradually decays over time despite continuous photo-activation and nuclear NICD accumulation, indicating dynamic adaptation to the signalling input. Using mathematical modelling and molecular perturbations, we show that this adaptive transcriptional response fits to known motifs capable of generating near-perfect adaptation and can be best explained by state-dependent inactivation at the target cis-regulatory region. Taken together, our results reveal dynamic nuclear adaptation as a novel mechanism controlling Notch signalling output during tissue differentiation.

中文翻译：

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通过细胞核中的动态适应使 Notch 信号脱敏

在胚胎发育过程中，信号通路通过控制组织特异性基因表达程序和分化来协调器官发生。尽管许多常见发育信号系统的分子成分是已知的，但我们目前对信号输入如何实时转化为基因表达输出的理解是有限的。在这里，我们采用光遗传学来控制果蝇期间 Notch 信号的激活以微小的精度进行胚胎发生，并通过定量实时成像跟踪目标基因的表达。Notch 细胞内结构域 (NICD) 的光诱导核易位导致目标 mRNA 表达的快速激活。然而，尽管持续的光激活和核 NICD 积累，靶基因转录随时间逐渐衰减，表明对信号输入的动态适应。使用数学建模和分子扰动，我们表明这种适应性转录反应适合能够产生近乎完美适应的已知基序，并且可以通过目标顺式的状态依赖性失活来最好地解释- 监管区域。总之，我们的结果揭示了动态核适应是一种控制组织分化过程中 Notch 信号输出的新机制。