THE NUCLEAR HORMONE-RECEPTOR FTZ-F1 IS A COFACTOR FOR THE DROSOPHILA HOMEODOMAIN PROTEIN FTZ

Homeobox genes specify cell fate and positional identity in embryos th roughout the animal kingdom(1). Paradoxically, although each has a spe cific function in vivo, the in vitro DNA-binding specificities of home odomain proteins are overlapping and relatively weak. A current model is that homeodomain proteins interact with cofactors that increase spe cificity in vivo(2,3). Here we use a native binding site for the homeo domain protein Fushi tarazu (Ftz) to isolate Ftz-F1, a protein of the nuclear hormone-receptor superfamily and a new Ftz cofactor. Ftz and F tz-F1 are present in a complex in Drosophila embryos. Ftz-F1 facilitat es the binding of Ftz to DNA, allowing interactions with weak-affinity sites at concentrations of Ftz that alone bind only high-affinity sit es. Embryos lacking Ftz-F1 display ftz-like pair-rule cuticular defect s. This phenotype is a result of abnormal ftz function because it is e xpressed but fails to activate downstream target genes. Cooperative in teraction between homeodomain proteins and cofactors of different clas ses may serve as a general mechanism to increase HOX protein specifici ty and to broaden the range of target sites they regulate.