Investigating the impact of XtSulf1 on canonical and non-canonical Wnt signalling

Cells in all animals are surrounded by a sticky matrix that holds them together and helps in relaying messages from one cell to another. We have found that when this matrix is modified messages can no longer be received by a cell or, on the other hand, sometimes messages are received more efficiently. We are working on a gene called XtSulf1 that makes an enzyme that re-structures the matrix on cells. We want to know whether this enzyme will change the ability of a cell to respond to a message called Wnt. We will investigate exactly what underlies the effects of XtSulf1 on Wnt. All the players involved in these processes are important and we want to determine what is happening at the level of the cell and the messages. The Wnt message is known to be important for embryos to develop properly, for stem cells to grow in culture and is also known to be mis-regulated in disease: therefore a good understanding of how this message can be controlled will be important in developing new medical therapies and for the advancement of regenerative medicine.

Heparan sulphate proteoglycans (HSPGs) are present on the cell surface and in the extracellular matrix in all animals. HSPGs bind avidly to many different proteins including growth factors and their receptors. XtSulf1 codes for an extracellular 6-O-endosulfatase that post-synthetically remodels HSPGs and is dynamically expressed during development. XtSulf1 can modulate the ability of a cell to respond to signalling. The research question addressed by this project is: What is the molecular mechanism by XtSulf1 modulates canonical and non-canonical Wnt signalling during embryonic development? HSPGs are known to be essential for cell signalling, however, a role for HSPGs as regulators of cell signalling is an exciting new principle that has recently come to light. Sulf1 remodelling of cell surface HSPGs influences their ability to promote or inhibit cell signalling. Sulf1 is known to be mis-regulated in human tumour tissue and this contributes to cancer progression because of its impact on cell signalling. Sulf1 also plays a role in providing a stem cell niche for adult myoblasts through its inhibition of signals that promote differentiation. While Sulf1 activity has been found to inhibit signals including FGF and BMP in developing embryos, Sulf1 is known to enhance Wnt signalling in tissue culture. However, we have preliminary findings that suggest the role of Sulf1 in modulating Wnt signalling is complex. We aim to establish the mechanism by which Sulf1 can modulate the ability of Wnt ligands to activate canonical and non-canonical signal transduction pathways which lead to distinct effects on gene expression and cell behaviour. Important roles for Wnt signalling in development and disease are well established and our investigation into the cellular and molecular mechanism by which Sulf1 activity impacts on Wnt signalling will provide novel insights to give direction to more applied research.

1. Researchers in many different fields are interested in Wnt signalling and how it regulates cell proliferation and differentiation, so beneficiaries will also include the biomedical sector investigating stem cell behaviour, regenerative medicine and tissue engineering, in addition to the academic beneficiaries listed above. 2. The project will provide excellent training for the RA employed to undertake the work. The RA will benefit from expertise within my lab on the in vivo approaches used in embryology, molecular biology and bioinformatics. Our department also has excellent training available through our technology facility. The Department of Biology also has an active career development programme for post-doctoral researchers, from which the RA on this grant will benefit. 3. A good public understanding of science is crucial for the continued rapid pace of scientific achievement, as this requires continued public support and funding from the public purse. I am actively engaged in outreach activities, reacting to opportunities as they arise and through participation in the Department's outreach programmes. The Department has recently instated a publicity officer to ensure breaking news about our research is publicised through the media, our web site and our new electronic news letter bio-LOG. I have been appointed Developmental Biology area co-ordinator for this effort and communicate local advancements in this area to the publicity officer.