Julian Lewis

Notch signalling dynamics, oscillations, and tissue patterning in a vertebrate embryo: mathematical modelling and experimental analysis

Developmental processes follow a well-defined timetable, but we understand remarkably little about how the timing is controlled. We are particularly interested in this problem in relation to the Notch cell-cell signalling pathway, which controls cell fate choices, cell diversification and stem-cell behaviour in almost every tissue of the body, from the embryonic brain to the adult gut.

For example, in the formation of somites (the embryonic rudiments of the segments of the vertebrate body), cells at the tail end of the embryo show oscillatory transcription of Notch pathway components, and the ticking of this molecular clock controls the size and spacing of the somites: each somite consists of the batch of cells emerging from the tail region in the course of one clock cycle (30 minutes in a zebrafish, two hours in a mouse).

We have proposed a mathematical model of how the somite oscillator works, and we have developed experimental tools to test this model in the zebrafish and to measure the key parameters. For example, we have generated transgenic fish in which we can abruptly switch on expression of key components by giving a heat shock, while other transgenic constructs enable us to follow the response using fluorescent reporter proteins.

We now wish to extend this work and apply similar methods, combining mathematical and experimental analysis, to investigate the control of developmental timing in other tissues, such as the central nervous system (where Notch signalling governs production of neurons) and the sensory epithelium of the ear (where it governs production of sensory hair cells).

Candidates with a background in the physical sciences, mathematics, or engineering, as well as biologists, are encouraged to apply: knowledge of molecular biology would an advantage but is not an absolute requirement - training can be provided. The key requirement is enthusiasm to learn to do experiments at the lab bench and to combine experimental and mathematical approaches to problems of cell and developmental biology.

References

Jiang Y-J, et al. Notch signalling and the synchronisation of the somite segmentation clock. Nature 2000; 408: 475-479.

Lewis J. Autoinhibition with transcriptional delay: a simple mechanism for the zebrafish somitogenesis oscillator. Curr Biol 2003; 13: 1398-1408.

Giudicelli F and Lewis J. The vertebrate segmentation clock. Curr Opin Genet Dev 2004; 14: 407-414.

Lewis J and Ozbudak EM. Deciphering the somite segmentation clock: beyond mutants and morphants. Dev Dyn 2007; 236: 1410-1415.

Giudicelli F, et al. Setting the tempo in development: an investigation of the zebrafish somite clock mechanism. PLoS Biol 2007; 5: e150.