Desensitisation of Notch signalling through dynamic adaptation in the nucleus

Abstract

During embryonic development, signalling pathways orchestrate organogenesis by controlling tissue-specific gene expression programmes and differentiation. Although the molecular compo- nents 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 expres- sion. However, target gene transcription gradually decays over time despite continuous photo-activation and nuclear NICD accu- mulation, 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 signal- ling output during tissue differentiation.