The Drosophila WIF1 homolog Shifted maintains glypican-independent Hedgehog signaling and interacts with the Hedgehog co-receptors Ihog and Boi

Hedgehog (Hh) family proteins are secreted signaling ligands whose short- and long-range activities transform cellular fates in multiple contexts in organisms ranging from metazoans to humans. In the developing Drosophila wing, extracellular Hh binds to cell-bound glypican heparan sulfate proteoglycans (HSPGs) and the secreted protein Shifted (Shf), a member of Wnt inhibitory factor 1 (WIF1) family. The glypicans and Shf are required for long-range Hh movement and signaling; it has been proposed that Shf promotes long-range Hh signaling by reinforcing binding between Hh and the glypicans, and that much or all of glypican function in Hh signaling requires Shf. However, we will show here that Shf maintains short-range Hh signaling in the wing via a mechanism that does not require the presence of or binding to the Drosophila glypicans Dally and Dally-like protein. Conversely, we demonstrate interactions between Hh and the glypicans that are maintained, and even strengthened, in the absence of Shf. We present evidence that Shf binds to the CDO/BOC family Hh co-receptors Interference hedgehog (Ihog) and Brother of Ihog, suggesting that Shf regulates short-range Hh signaling through interactions with the receptor complex. In support of a functional interaction between Ihog and members of the Shf/WIF1 family, we show that Ihog can increase the Wnt-inhibitory activity of vertebrate WIF1; this result raises the possibility of interactions between WIF1 and vertebrate CDO/BOC family members.