Pass the Wnt, from secretion to signalling

A relatively small number of proteins have been suggested to act as morphogens, molecules that spread within tissues to organize cell fate decisions and tissue repair. Among them are Wnt proteins, which, surprisingly for signalling molecules, are relatively insoluble because of a palmitoleate moiety that is essential for signalling activity. A number of proteins are dedicated to Wnt secretion and transport in the extracellular space. In particular, Wntless escorts Wnt from the ER to the cell surface, and Dlp-class glypicans shield the Wnt lipid in the extracellular space before it engages with signalling receptors of the Frizzled family. We will combine structural, biophysical, and genetic approaches to characterise the key interactions that Wnt proteins and their lipid engage with during this journey. Thus, we will determine how Wnts are released from Wntless in secreting cells and allowed to form a complex with Dlp-class glypicans. We will determine the glycosaminoglycans that support the formation of the Wnt-glypican complex before elucidating the complex’s structure and identifying the key determinants of affinity. These measurements will lead to a mechanistic understanding of Wnts’ extracellular transport and subsequent hand-over to Frizzleds and form the foundation of a realistic mathematical model of Wnt gradient formation.