Final Report Summary - WNTEXPORT (Sorting processes that ensure short and long-range action of Wnts in developing epithelia)
Cell to cell signalling is essential for both normal development and tissue homeostasis during adult life. However, excess signalling often leads to disease such as cancers. This is true for Wnt proteins, a class of signalling molecules that control growth and patterning during development and are essential for stem cell maintenance in a variety of tissues such as the gut, while excess Wnt signalling is associated with numerous cancers. It is therefore essential for Wnt signals to reach the right cells are the appropriate level (just-right signalling). Through our project, we have made important contributions to understanding how the range and activity of Wnt are regulated. How far Wnt proteins act has been a long-standing question. Wnt proteins are appended with a lipid during synthesis, making them hydrophobic and therefore unlikely to spread unaided in the aqueous extracellular space. Yet, several lines of evidence have suggested that Wnt could act over a long range. We have used Drosophila to devise a clear genetic test of whether Wnts do need to spread. This was achieved by modifying the genome so that the endogenous wingless locus produces a transmembrane protein. The resulting flies were surprisingly well formed suggesting that Wnts may not need to spread for many of their functions. These flies had mild defects that may help us identify tissues where the release of Wingless is needed. It is conceivable that in these areas, specific carriers, perhaps exosomes, are at work. Another achievement of our project has been to elucidate, in collaboration with structural biologists, the mode of action of Notum, a secreted protein that dampens Wnt signalling. We have shown that this protein, which is produced in response to Wnt signalling, removes the lipid from Wnts. Since this lipid is essential for signalling activity, Notum behaves as a secreted feedback inhibitor. We have shown that Notum requires glypicans for this activity and have suggested that glypicans act as an introductory agency by bringing Wnts and Notum in close proximity. Our structural information is informing the design small molecule inhibitors, which could be used as pharmacological agents to boost Wnt signalling, e.g. to enhance stem cells maintenance in intact tissues