£1M MRC funding to study the earliest stages of development

The £1M funding will support understanding the earliest stages of development, which if it occurs incorrectly can lead to birth defects such as scoliosis and certain cancers.

The project will investigate a specific process in the developing embryo called segmentation. This is where distinct groups of cells periodically separated off from a rod of tissue at the tail of the embryo. The resulting segments (called somites) later form the bones and muscles of the skeleton.

The periodicity of segmentation is regulated by the periodic expression of a set of genes known as the segmentation clock. These genes need to be switched on and off in a timely fashion to generate the correctly timed waves of clock gene expression. Together, these regulate the timing of the formation of the segments. If the segmentation clock genes are not switched on and off at the correct times this results in bigger or smaller segments which can lead to birth defects such as scoliosis.

Dr Hedda Meijer, co-investigator on the project explains, “Regulation of gene expression occurs at several different levels. When genes are activated, a copy is made of the desired gene: the messenger RNA, which then subsequently gets translated into the protein that is required. For the segmentation clock a lot is known about how the genes are activated but our knowledge on how the activity levels and stability of these messengers are regulated is very limited. This is what this project hopes to address.”

Dr Philip Murray, co-investigator on the project explains, “Almost all the existing mathematical models of the segmentation clock describe how clock protein inhibits clock gene transcription via a negative feedback loop. However, regulation of mRNA degradation and translation in most existing models is usually assumed to be a linear process. We have previously published a model that demonstrates that nonlinear regulation of mRNA activity can lead to exciting dynamical behaviours. In this proposal we will perform experiments that challenge the ‘linear mRNA regulation’ framework. Based upon the experimental findings we will return to theoretical model and update accordingly.” The project aims to identify the regulatory processes governing regulation of messenger activity and stability of segmentation clock genes. 
Accurate regulation of messenger activity and stability are critical to determine the timing and the amount of the proteins that will be made and are essential for successful segmentation and embryonic survival.

Hedda continues, “We will use stem cell derived model systems that facilitate research into the development of human embryogenesis without the use of human or animal embryos. This system will allow us to analyse how mRNA regulation affects somite formation in a human developmental context. It will provide greater understanding of the mechanisms regulating the ‘correct’ amount of the messengers and proteins made by clock genes. It will also inform our understanding of how mis regulation of those processes may contribute to certain developmental disorders and cancers.”

This research involves co-investigators Dr Philip Murray (Mathematics) and Dr Hedda Meijer (SLS-MCDB) and collaborators from the MRC Protein Phosphorylation and Ubiquitylation Unit in Dundee, the Francis Crick Institute and the University of Nottingham. Facility expertise will be provided by the School’s Stem Cell Facility and Data Analysis Group.