Glypicans define unique roles for the Hedgehog co-receptors Boi and Ihog in cytoneme-mediated gradient formation

The conserved family of Hedgehog (Hh) signaling proteins plays a key role in cell-cell communication during development, tissue repair and cancer progression, inducing distinct concentration-dependent responses in target cells located at short and long distances. One simple mechanism for long distance dispersal of the lipid modified Hh is the direct contact between cell membranes through filopodia-like structures known as cytonemes. Here we have analyzed in Drosophila the interaction between the glypicans Dally and Dally-like protein, necessary for Hh signaling, and the adhesion molecules and Hh coreceptors Ihog and Boi. We describe that glypicans are required to maintain the levels of Ihog, but not of Boi. We also show that the overexpression of Ihog, but not of Boi, regulates cytoneme dynamics through their interaction with glypicans, the Ihog fibronectin III domains being essential for this interaction. Our data suggest that the regulation of glypicans over Hh signaling is specifically given by their interaction with Ihog in cytonemes. Contrary to previous data, we also show that there is no redundancy of Ihog and Boi functions in Hh gradient formation, being Ihog, but not of Boi, essential for the long-range gradient.Spanish Ministry of Science, Innovation and Universities and by institutional grants from the Fundación Areces and from Banco de Santander to the CBMSO. FPI fellowship from the Spanish Ministry of Science, Innovation and Universities supported CJ (BFU2017-83789-P), AA-T (BFU2014-59438-P)