Decoding the Notch signal

The human body is composed of millions of cells which have to be assembled and maintained correctly. For this complex assembly process to happen, the cells need to communicate with each other. They do so via special types of signals. One such signal uses a protein called Notch as its receiver. Messages sent through Notch can make cells proliferate or change their behaviours, and sometimes even die. What we don?t understand is how Notch can communicate such different messages at different times. This is of major importance because we now know that inappropriate activity of Notch is responsible for several types of cancers and is linked to other disease too. The goal of our work is to understand the language of the different messages that Notch sends at different times and to identify particular ?signatures? that will be helpful in clinical situations to show whether Notch is working inappropriately. If it is, this may influence what treatments should be provided. In addition, the ?letters? within a signature could give us good clues about ways to develop new drugs for particular cancers in future.

We do most of our experiments using the fruitfly, which gives us a simpler model to decode these different messages. Because there are very big similarities between the ways cells work in flies and people (Notch was first found in fly studies and ~80% of disease causing genes can be found in flies) we are confident that the fly experiments will give us a route to important tools for use in the clinic.

Signalling through the Notch receptor controls many different decisions in development, contributes to the maintenance of tissues in the adult and is associated with a number of diseases, including cancers. Despite its simple transduction pathway, Notch activation elicits different consequences in these different contexts, for example sometimes causing proliferation, sometimes cell-death. Our goal is to investigate the molecular basis for this diversity. Through a combination of genomic and genetic approaches, primarily using Drosophila as our model, we aim (I) to discover the relevance of novel Notch targets in development and disease (II) to investigate the diversity of responses in different tissues; (III) to determine mechanisms that cause different types of target-genes to be activated in different contexts. Together these studies will make a major contribution to our understanding of the differential consequences of activating Notch and, given the conservation between flies and humans, are likely to uncover new markers or mechanisms of regulation that could prove valuable for clinical use and intervention.