Exploring the role of glypicans in modulating morphogen signalling and stem cell dynamics

Wnt and Hedgehog signalling regulate intestinal stem cell dynamics to ensure intestinal renewal, function and integrity is maintained.

The activation of these two pathways involves crosstalk and communication between the mesenchymal and epithelial layers of the intestine.

However, a puzzling conundrum is that both Wnt and Hedgehog carry hydrophobic lipid moieties that are required for receptor binding and signalling but that also hinder their solubility and diffusion and hence ability to move between intestinal cells.

In Drosophila, the glypican Dally-like protein (Dlp), which possess a lipid binding pocket, binds and shields the lipid moiety of Wnts to aid transport. Dlp is also essential for initiating Hedgehog signalling but its precise mechanism of action is unknown.

I will determine if Dlp also binds the lipid moieties of Hedgehog and what such binding means for Hedgehog solubility, transport and receptor engagement.

I will determine if mammalian homologues of Dlp also bind the lipid moieties of Wnt and Hedgehog to regulate their activity and whether they are required in the mouse intestine for Wnt and Hedgehog signalling to orchestrate stem cell dynamics.

A deep understanding of how glypicans modulate Wnt and Hedgehog signalling will answer major questions in developmental and stem cell biology.