Deciphering Notch signalling dynamics in vivo (360G-Wellcome-212207_Z_18_Z)

To make and organize different tissues, cells must decipher information from developmental signalling pathways. Transmitting this information accurately, so that cell-surface signals are translated into correct transcriptional responses, is of critical importance but how this is achieved mechanistically remains a major question. We propose to answer this focussing on the Notch pathway. Dosage and dynamics of Notch activity are fundamentally important for developmental decisions and tissue homeostasis and their mis-regulation underlies many diseases including cancers. Our ability to image events in real time within living fly embryos gives us a powerful system to investigate dynamic properties of Notch signalling in physiological conditions. Our overall goal is to decipher temporal, quantitative and mechanistic principles that govern how Notch activity is read by target enhancers in the living animal. Using cutting-edge strategies for measuring transcription responses and complexes we will address: (i) how Notch signals are decoded in real time in vivo, (ii) what mechanisms/partners are required to accurately transduce Notch signals, (iii) what roles tissue geometry and forces play in shaping signalling dynamics. Answers will provide new insights for manipulating Notch in a controlled way, enabling strategies for altering cell fates or for treating diseases driven by aberrant Notch signalling.