An RNAi-based screen in Drosophila had previously identified CG9211 as a component of the Hedgehog pathway. Yao et al. now identify this gene as encoding interference hedgehog (Ihog) and define this as the founding member of a family of proteins that have a single transmembrane domain, extracellular immunoglobulin (Ig) domains, and fibronectin domains and that bind extracellular ligands of the hedgehog (Hh) family. The other members are brother of Ihog (Boi) in flies and CDO and BOC in mammals. Flies with mutant ihog alleles exhibit patterning defects associated with loss of Hh signaling, and epistasis analysis in cultured cells places ihog upstream or at the same level as the Hh receptor Patched (Ptc). Ihog was detected on the surface of embryonic Drosophila cells and the S2 Drosophila cell line and appears to be a glycoprotein. Fusion proteins of the extracellular region of Ihog or Boi interacted with HhN (the lipid-modified form of Hh) from conditioned medium. Binding of a tagged form of HhN to COS1 monkey cells was increased severalfold by the cotransfection of Ptc and Ihog and was higher than when HhN was applied to cells transfected with either Ptc or Ihog individually. Binding of the mammalian Sonic hedgehog (ShhN) was also observed in vitro using fusion proteins of BOC or CDO, and knockdown of CDO or BOC using RNA interference techniques inhibited the activation of a ShhN-regulated reporter gene. Thus, Ihog defines a new family of Hh receptors that appear to act synergistically with Ptc to initiate signaling through the Hh pathway.
S. Yao, L. Lum, P. Beachy, The Ihog cell-surface proteins bind hedgehog and mediate pathway activation. Cell 125, 343-357 (2006). [Online Journal]