University of Dundee

4 Year MRC PhD Programme: Developing a scalable, high throughput model system for the study of segmentation defects

During somitogenesis, a process that is fundamental to the development of the vertebrate body plan, the embryo sequentially forms pairs of somites at periodic intervals in time. Somites are epithelial spheres that later give rise to the ribs and vertebrae of the skeleton, associated skeletal muscle and some dermis. The temporal periodicity of somite formation is regulated by a molecular oscillator known as the somitogenesis clock. Abberations to somitogenesis lead to a variety of congenital vertebral malformations including spondylocostal dysostosis (SCD).

 

In general, developmental systems can be used to understand the conditions necessary for the generation of biological tissue. However, such translation is limited by factors such as small sample sizes of tissue with which to perform experiments and, for ethical reasons, our inability to study human developmental tissue.

 

The proposed PhD project aims to address these issues. Using mouse as a model system we will generate presomitic mesoderm cells in vitro from mouse embryonic stem cells. The embryonic stem cells will be derived from a transgenic mouse line that carries unstable VENUS GFP downstream of the promoter of a somitogenesis clock gene. We will house large numbers of tissue samples in a bespoke microfluidic apparatus, analyse clock oscillations and use the datasets to improve upon existing mathematical models.

 

We will use the in vitro somitogenesis system to study how the deletion of the homologues of genes known to be required for normal human segmentation affects PSM tissue behaviour and attempt to rescue the phenotype. Hence knowledge gained will provide insight into the underlying mechanisms giving rise to SCD.

 

The student will obtain training in stem cell biology, developmental biology, data analysis and mathematical modelling of the somitogenesis oscillator.

 

References:

1. Gouti M., et al. (2014). PLoS Biol   12.8 e1001937.

2. Lauschke V, et al.  (2013). Nature. 493.7430 101-105.

3.  Wiedermann G, Bone, R, Clara J, Bjorklund M, Murray PJ, and Dale JK (2015) eLife 10.7554/eLife.05842

 

 

 

 

 

 

 

Eligibility