The Hedgehog (Hh) signal can function during development as a morphogen, so its concentration and distribution must be tightly regulated. Two groups — Gorfinkiel et al. and Glise et al. — report in Developmental Cell the characterization of Shifted (Shf), a secreted protein that is required to control the movement of Hh in Drosophila melanogaster.

Both groups analysed the function of shf in Hh signalling in the developing wing as a model system. Known mutations in shf caused defects that were similar to those of mutants that are known to affect the release, transport or modification of Hh. Both groups found that the levels of Hh protein were reduced, as was the range of Hh movement and the resultant signalling. This indicated that Shf was required for both the accumulation or stability of Hh and its movement within the wing disc from the posterior compartment (Hh-producing cells) to the anterior compartment (Hh-receiving cells).

Further characterization of the shf locus by both groups showed it to encode the D. melanogaster orthologue of the vertebrate Wnt inhibitory factor-1 (WIF-1). Both proteins have an N-terminal signal sequence, a WIF domain and five epidermal growth factor (EGF)-like repeats. In addition to the presence of the signal sequence — an indicator of secretion — non-autonomous rescue experiments and immunofluorescence indicated that Shf was secreted.

Both groups also observed a relatively higher level of Shf in cells of the posterior compartment, which depended on the presence of Hh. And Gorfinkiel et al. were able to co-immunoprecipitate Shf and Hh. Both sets of authors surmised that Shf might mediate the interaction between Hh and heparan sulphate proteoglycans (HSPGs), which, like Shf, are necessary for the normal accumulation and movement of Hh. And, indeed, Glise et al. showed that changes in HSPGs affected Shf accumulation (as well as Hh distribution).

In vertebrates, WIF-1 inhibited Wnt signalling, but both groups agreed that Shf modulates the distribution of Hh without affecting Wnt signalling. Gorfinkiel et al. further showed that human WIF inhibited signalling by the Wnt-family member Wingless in D. melanogaster without affecting the Hh pathway. So different WIF-family members might have divergent functions in each pathway.