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

Reference	BB/W017032/1
Principal Investigator / Supervisor	Professor Andrea Munsterberg
Co-Investigators / Co-Supervisors	Professor Grant Wheeler
Institution	University of East Anglia
Department	Biological Sciences
Funding type	Research
Value (£)	421,978
Status	Current
Type	Research Grant
Start date	01/09/2022
End date	31/08/2025
Duration	36 months

Abstract

The canonical Wnt pathway is a potent signalling system that regulates numerous processes during embryonic development, including cell fate determination, migration, polarity, proliferation, and apoptosis, as well as stem cell biology and adult tissue homeostasis. Dysregulated Wnt signalling contributes to many diseases, including birth defects, neurodegeneration, and cancers. As a result, investigation of the Wnt pathway, and identification of Wnt regulators, is considered a research priority. Lipid modifications are rapidly emerging as critical regulators of nearly every step in the canonical Wnt pathway. However, the nature, regulation and significance of such modifications remains poorly understood. We recently discovered that alkylglycerol monooxygenase (AGMO), the only enzyme known to cleave the O-alkyl ether bond in alkylglycerols, is an critical regulator of Wnt signalling in the embryo. Ether lipids were not previously implicated in Wnt signalling or embryo formation. Here, we will use a unique combination of live imaging, lipid metabolic tracing, and developmental biology to identify and investigate agmo requirements during embryogenesis, and determine precisely how agmo regulates the canonical Wnt signalling pathway. We will also test whether supplementation with fatty acids lacking in agmo mutants can rescue the developmental phenoptypes. Completion of these objectives will identify a novel mechanism of Wnt signal regulation and transform our understanding of the role ether lipids play in development and disease, opening up new avenues of investigation.

Summary

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.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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