shifted, the Drosophila homolog of the human Wnt inhibitory factor 1, is involved in the Hedgehog signaling pathway

The Hedgehog signaling pathway is important in patterning the anterior-posterior axis of the embryonic and adult cuticle of the fruitfly Drosophila melanogaster. Though great strides have been made in understanding the intracellular signaling cascade, many questions remain in the production of the extracellular gradient. Through the study of shifted we hope to extend our knowledge of the extracellular modulation of Hh signaling.;Study of the shf mutant was undertaken based upon the observation that the narrowing of the intervein, between longitudinal wing veins L3 and L4, is reminiscent of the phenotype seen when there is a decrease in the Hh signal. Genetic interaction studies and an examination of Hh target expression indicate that Shf is involved in Hh signaling. Upon cloning of the shf locus, it was found to encode the Drosophila homolog of the human Wnt inhibitory factor 1, a secreted factor that was shown to inhibit Wingless-Wnt signaling. There is no indication for Shf acting in canonical Wingless signaling. Overexpression studies of the six other Drosophila Wnt homology also argue against a Shf-Wnt interaction in Hh signaling.;The role of Shf in Hh signaling appears to control the range of the Hh gradient. This is based upon the fact that Hh targets in a shf 2 background retain a nested pattern of expression, even though the expression domains have narrowed. I discuss three possible models for Shf's action on Hh activity. One model for controlling Hh activity is direct binding to Hh to control Hh signal potential. The two other possibility include the Hh receptor Smoothened (Smo). The homology of Smo to the Wnt receptor Frizzled had suggested a Smo-Wnt interacton and the lack of Wnt inhibition suggests that it could act to assist a Wnt-Smo interaction. The other suggestion is that Shf is a ligand for Smo signaling and could act in a Smo-LRP receptor complex.