Direct cell-to-cell transport of Hedgehog morphogen is aided by the diffusible carrier Shifted/DmWif1

The establishment of morphogen gradients is fundamental during embryonic patterning. Yet, the mechanisms by which morphogens disperse remain highly controversial. In a paradigmatic example, the dispersal of the morphogen Hedgehog (Hh) is both limited by and dependent on its lipid modifications. To address this paradox, several competing transport models have been proposed, ranging from lipid-shielding solubilising factors to transport via specialized filopodia called cytonemes. In this study, we uncover that the lipid-shielding protein DmWif1/Shifted (Shf) participates in the contact-dependent cell transfer of Hh. Using nanobody-based immobilisation of natural and synthetic ligands, we demonstrate the tight association of Shf and Hh to cytoneme membranes. We show that Shf is anchored to membranes by the Hh co-receptor Interference Hedgehog (Ihog) and that the Ihog-Shf complex is required for Hh dispersal and signalling. Together, our results suggest a unified dispersal model combining cytoneme-mediated transport and membrane release, in which local solubilisation facilitates the transfer of Hh-Shf complexes at cell-cell contacts between presenting and receiving cytonemes.