Cholesterol-free and cholesterol-bound Hedgehog: Two sparring-partners working hand in hand in the Drosophila wing disc?

Hedgehog (Hh) is a signaling ligand conserved from flies to humans that is covalently bound to both palmitate and cholesterol moieties. These lipid modifications are crucial for Hh signaling. A recent article reports that in both flies and human-cultured cells a cholesterol-free form of Hh (SHh-N*/Hh-N*) is produced and secreted. In the Drosophila wing disc, Hh associated with Lipoproteins-lipophorin complexes (Lpp) would lead to the accumulation of Cubitus interruptus (Ci), the transcription factor in the Hh pathway but this would be insufficient to activate Hh target genes. On the other hand, Lpp-free Hh-N* would act in synergy with Lpp-associated Hh to eventually activate target gene expression. This suggests that Hh can be secreted in 2 different forms that would have distinct and synergic functions.