Notch Signalling and the Patterning of Tissues in Space and Time

Previous and current research
Neighbouring cells in a multicellular tissue have to coordinate their patterns of gene expression. For this, they must communicate, exchanging gene-regulatory signals. Of all the mechanisms for one cell to influence gene expression in its immediate neighbours, Notch signalling is arguably the most direct. This fundamental mechanism of cell-cell communication operates, intermittently, in almost every tissue, in every multicellular animal. To understand how tissues become organised during development, maintain their organisation during tissue renewal, and suffer disorganisation in cancer and other diseases, we need to understand how Notch signalling works, where and when it is brought into play, and what functions it performs in specific situations. The Notch signalling pathway is not just a telephone line from the surface of one cell to the nucleus of its neighbour: it also provides fundamental mechanisms for breaking symmetry and generating pattern in multicellular systems, as our past work has helped to show. The components of the pathway can be linked together to form a variety of different gene-regulatory circuits, including positive and negative feedback loops. These feedbacks are the basis for lateral inhibition, through which an array of initially similar cells can organize itself into a pepper-and-salt mixture of different cell types. Feedbacks in the Notch pathway are also responsible, we believe, for the remarkable temporal oscillations of gene expression that control the segmentation of the vertebrate body. We aim to understand, through experimentation and through mathematical modelling, how these feedbacks operate to govern tissue patterning not only in space, but also in time. Four systems interest us in particular: the sensory epithelium of the inner ear with its beautiful arrays of sensory hair cells and supporting cells; the lining of the gut and its remarkable Notch-dependent stem-cell system; the developing vasculature; and the presomitic mesoderm with its somite segmentation clock. The zebrafish is our main model organism.

Future projects
Our current work has two chief goals. First, we want to define the part that Notch signalling plays in controlling cell fate choices and cell proliferation in tissues such as the gut lining that undergo renewal from stem cells. For this, we have developed a new tool for clonal analysis of gene function in the zebrafish, allowing us to create, at any desired stage, clones of cells that are heritably marked with RFP and at the same time express a chosen transgene or combination of transgenes. Our second main goal is to provide a quantitative, mathematically formulated, and experimentally validated account of the dynamics of the feedback circuitry based on the Notch signalling pathway. In particular, we seek to understand its role in controlling the timing of developmental events, with special reference to the somite segmentation clock and the inner ear / lateral line. The control of timing in development is very poorly understood. Through study of Notch signalling we aim to get insight into the general problem.