An acylatable residue of hedgehog is differentially required in Drosophilaand mouse limb development

The Drosophila Hedgehog protein and its vertebrate counterpart Sonic hedgeh og are required for a wide variety of patterning events throughout developm ent. Hedgehog proteins are secreted from cells and undergo autocatalytic cl eavage and cholesterol modification to produce a mature signaling domain. T his domain of Sonic hedgehog has recently been shown to acquire an N-termin al acyl group in cell culture. We have investigated the in vivo role that s uch acylation might play in appendage patterning in mouse and Drosophila; i n both species Hedgehog proteins define a posterior domain of the limb or w ing. A mutant form of Sonic hedgehog that cannot undergo acylation retains significant ability to repattern the mouse limb. However, the corresponding mutation in Drosophila Hedgehog renders it inactive in vivo, although it i s normally processed. Furthermore, overexpression of the mutant form has do minant negative effects on Hedgehog signaling. These data suggest that the importance of the N-terminal cysteine of mature Hedgehog in patterning appe ndages differs between species. (C) 2001 Academic Press.