Functional analysis of alkylglycerol monooxygenase; an unexpected modulator of Wnt signalling and embryogenesis

点击翻译按钮获取中文摘要

The big picture: for an embryo to develop normally, or an adult to function correctly, cells need to communicate with each other. This communication tells cells what they should do. The Wnt signalling pathway is a cellular communication system that plays important roles in telling cells how to behave during development of an embryo. Impaired Wnt signalling causes birth defects and contributes to numerous adult diseases, including cancers. As such, it is important we understand how the Wnt pathway works so that we can discover ways to control it and potentially find new ways to treat disease.Proteins in the Wnt pathway can be modified by cells to control how they function. Almost every step in the Wnt signalling pathway is regulated by the attachment or removal of small lipids. However, despite the importance of these lipid modifications, our understanding of how they occur and how they control Wnt signalling remains very limited. In part this is because it is difficult to find the genes making these modifications. We recently discovered that a gene named amgo, which encodes the only enzyme known to cut a particular type of lipids (called ether lipids), is a regulator of Wnt signalling and is required for normal development of the embryonic heart. We also have preliminary evidence that agmo plays an important role in development of the head, brain and muscles. Furthermore, combinations of neural, cardiac, muscle and facial abnormalities have been identified in over 25 human patients with mutations in agmo. However, we still know very little about how agmo functions, or how ether lipids are needed to form an embryo. In this project we will investigate the role of agmo in Wnt signalling and development.In Objective 1, we will determine whether agmo is really required for normal development of the head, brain and muscles? We will do this by decreasing agmo levels in tadpoles and chick embryos and using state of the art imaging and molecular biology assays to see if development of these structures is altered.In Objective 2, we will investigate how agmo affects the Wnt signalling pathway. In particular, we will use a series of molecular experiments to discover the step in the pathway where agmo is needed, and the mechanism by which it regulates Wnt signalling.Finally, in Objective 3 we will precisely measure how agmo depletion is affecting embryonic lipid metabolism. Once we have identified where the pathway goes wrong in agmo depleted frogs, we will then test whether we can correct this metabolic problem to prevent the Wnt signalling problems and birth defects.Together, these experiments will reveal how a new and powerful regulator of the Wnt pathway works. We think that our discoveries have the potential to transform our understanding of the Wnt pathway, and we hope to open up new avenues of basic and therapeutic research.