The effects of Sulf1 on canonical and non-canonical Wnt signalling in Xenopus

Heparan sulphate proteoglycans are large macromolecules expressed on the cell surface. They are an important part of the extracellular matrix and regulate multiple cell signalling pathways. Sulf1 is an extracellular sulfatase that specifically removes 6-O linked sulphate groups from heparan sulphate chains. The activity of Sulf1 alters the ability of heparan sulphate chains to regulate FGF, BMP, hedgehog and Wnt signalling pathways. The original work that identified Sulf1 (Dhoot et al., 2001), demonstrated that Sulf1 enhanced the ability of Wnt1 to activate canonical Wnt signalling. This thesis uses Xenopus to investigate the effects of Sulf1 on canonical and non-canonical Wnt signalling in the early embryo. Sulf1 has ligand specific effects on different Wnt ligands, inhibiting the ability of Wnt8a, but not Wnt3a, to activate canonical Wnt signalling. In addition Sulf1 potentiates the ability of Wnt4 to activate non-canonical Wnt signalling and Wnt11b to activate both canonical and non-canonical Wnt signalling. Confocal analysis of animal caps expressing fluorescently tagged Wnt ligands shows that Sulf1 can enhance the range of diffusion of both Wnt8a and Wnt11b. The ability of Sulf1 to regulate Wnt ligand diffusion may explain some of the differential effects of Sulf1 on Wnt signalling. The results described in this thesis are discussed in terms of Sulf1 regulating Wnt morphogen gradients during development. The differential effects of Sulf1 on canonical and non-canonical Wnt signalling described here requires more than the existing ‘catch and present’ model (Ai et al., 2003). A new model is presented here.