PRONO · Notch and epithelial proliferation

During development the different organs and tissues of an organism have to grow harmoniously to reach their specific shapes and sizes. In the adult, organs have usually reached an equilibrium, where loss of cells must be compensated by tightly regulated proliferation. During cancer, groups of cells evade these controls and start to proliferate abnormally.The Notch intercellular signalling pathway is very conserved throughout evolution and directs a wide variety of cell fate decisions and behaviours. The specificity of outcome relies on the implementation of different transcriptional programmes. For instance, in certain epithelia from very diverse animals, Notch controls epithelial cell proliferation and tissue growth. In order to identify the genes mediating this effect of Notch, using genomic approaches, I have identified the direct Notch targets during wing discs hyperplasia in Drosophila. Functional analysis revealed complex cross regulation between targets and feed forward logic loops. What are the important functional nodes of the network of genes activated by Notch, and how does it operate?The current proposal seeks to reach an unprecedented detailed description of the Notch network mediating epithelial proliferation in Drosophila both during hyperplastic and neoplastic growth. More specifically, and using a combination of genome-wide approaches and elegant functional validation through Drosophila genetics, my aims are:- describe the global microRNAs response to Notch in hyperplastic Drosophila wing discs and understand how it shapes the Notch network during hyperplasia;- understand how this network is reshaped during the transition from hyperplastic to neoplastic growth, and identify a neoplastic specific programme;Critical aspects of the Notch network governing tissue growth, are likely to be conserved. Therefore, insights coming from our fly studies will drive new hypothesis to understand Notch driven tumorigenesis of human solid cancers.