Somites and patterning of the vertebral column

Malformations of the vertebral skeleton are very common in humans. As many as 10% of adolescent females may be affected by scoliosis, in addition to which there are many other musculo-skeletal problems of varying severity. We know very little about the causes of these anomalies, except that they are all due to some problem that happens during development of the cells that produce the vertebrae in the embryo. These cells are arranged into blocks, called somites. Deviations of the spine appear to be due to a local defect in somite size, for example affecting a somite on the left and not on the right. This project investigates the mechanisms that determine somite size and the rate at which they form. It also explores the relationship between the initial pattern of somites and the mature vertebrae that form from them. The results obtained will be very important for designing new diagnostics potential therapies.

The vertebrae that make up the axial skeleton arise from blocks of mesodermal cells in the embryo, called somites. However we know very little about the mechanisms that regulate their size and spatial arrangement. Expression of a number of genes (mainly in the Notch pathway) cycles at the same rate as somite formation in pre-somitic cells, and it is thought that this ?segmentation clock? regulates the size of somites. However this has not been tested directly, and several observations suggest that this clock could function instead to specify of the identity of cells in the rostral and caudal halves of the somite. The first part of this project takes advantage of a new experimental paradigm to separate the rhythmicity of somite formation from segmentation itself and explore the effects on somite patterning. After somites form, it is also widely assumed that one somite contributes to two adjacent vertebrae by a process of ?re-segmentation?. Although this has been tested by several studies, none of them have proved conclusive. The second part of the project investigates this directly using novel fate mapping approaches. Finally, the third part of the project explores the possibility, suggested by recent results, that some of the instructions for patterning may arise from the notochord (which mainly contributes to the intervertebral nucleus pulposus).