Members of the Hedgehog (Hh) and Wnt/Wingless (Wg) families of secreted proteins control many aspects of growth and patterning during animal development1,2. Hh signal transduction leads to increased stability of a transcription factor, Cubitus interruptus (Ci)3,4, whereas Wg signal transduction causes increased stability of Armadillo (Arm/β-catenin)5, a possible co-factor for thetranscriptional regulator Lef1/TCF6. Here we describe a new gene, slimb (for supernumerary limbs), which negatively regulates both of these signal transduction pathways. Loss of function of slimb results in a cell-autonomous accumulation of high levels of both Ci and Arm, and the ectopic expression of both Hh− and Wg− responsive genes. The slimb gene encodes a conserved F-box/WD40-repeat protein related to Cdc4p, a protein in budding yeast that targets cell-cycle regulators for degradation by the ubiquitin/proteasome pathway7,8,9. We propose that Slimb protein normally targets Ci and Arm for processing or degradation by the ubiquitin/proteasomepathway, and that Hh and Wg regulate gene expression at least in part by inducing changes in Ci and Arm, which protect them from Slimb-mediated proteolysis.
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We thank A. Adachi and Q. Zhou for technical assistance; W. Strapps for help with western analysis; S. Carroll, S. Cohen, R. Holmgren, M. Peifer, M. Hoffman, G. Panganiban and T.Kornberg for antibodies; the Bloomington stock centre for fly stocks; and I. Greenwald, T. Jessell, R.Mann and A. Tomlinson for discussion and comments on the manuscript. J.J. is an NIH postdoctoral trainee; G.S. is an investigator of the Howard Hughes Medical Institute.
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