Direct targets of Notch signalling activity

For cells in the body to know what tissue they are part of, whether to grow, they need to communicate. The Notch receptor is central to one communication pathway and is essential for our bodies to be made with the right number and types of cell. It is also important throughout our lives because overactive Notch receptors are the cause of some cancers and defective Notch causes other diseases including types of dementia.
In each cell-type in the body, only a small fraction of our genes are turned on. When Notch is active it results in additional genes being turned on. We are aiming to find out the identity of these additional genes and to investigate whether this can help us understand why Notch causes cells to change their behaviour and become cancerous.
Our model is the fruit-fly Drosophila melanogaster, where Notch was first identified. Recent sequence of human and Drosophila genomes shows that over 2000 human disease genes are conserved in flies. As Drosophila has fewer genes, fewer cells and is easy to work with, it provides a good starting-point to identify genes that are important in cancers and that could be important therapeutic targets.

Intercellular signalling via the Notch pathway is essential at many steps in the development of an animal as well as during post-natal life. Furthermore, correct regulation of this pathway is crucial, since aberrant Notch activity is associated with many types of human diseases including delayed onset dementia and cancers. Although it is clear that the changes in cell behaviour elicited by Notch activation involve rapid alterations in gene expression, very few genes controlled by Notch have been characterised to date. The overall aim of our proposal is to discover how Notch signalling leads to specific changes in cell behaviour by identifying the genes that are activated in different cell types and assessing how they contribute to the Notch response. Using Drosophila as a model we will: 1) use microarray approaches to systematically identify new Notch target genes, 2) validate these genes as Notch targets within the developing animal 3) study the developmental and biological function of a selected set of target genes, focussing on their contribution to Notch mediated processes and testing their conservation in mouse. Identification of such targets will be vital for understanding different functions of Notch during development and in human diseases.