In an attempt to understand development and differentiation processes of the parasitic blood fluke Schistosoma mansoni. several members of the nuclear receptor superfamily were cloned, including SmFtz-Fl (S. mansoni Fushi Tarazu-factor 1). The Ftz-FI nuclear receptor subfamily only contains orphan receptors that bind to their response element as monomers. Whereas SmFtz-FI displays these basic functional properties, we have identified an original and specific interaction between SmFtz-FI and the schistosome RXR homologue, SmRXR1. The mammalian two-hybrid assay showed that the D, E, and F domains of SmFtz-Fl were capable of interacting specifically with the E domain of SmRXR1 but not with that of mouse RXRalpha. Using three-dimensional LBD homology modelling and structure-guided mutagenesis, we were able to demonstrate the essential role of exposed residues located in the dimerization interfaces of both receptors in the maintenance of the interaction. Cotransfection experiments with constructions encoding full-length nuclear receptors show that SmRXR1 potentiates the transcriptional activity of SmFtz-Fl from various promoters. Nevertheless, the lack of identification of a dimeric response element for this SmFtz-FI/SmRXR1 heterodimer seems to indicate a "tethering" mechanism. Thus, our results suggest for the first time that a member of the Ftz-FI family could heterodimerize functionally with a homologue-of the universal heterodimerization partner of nuclear receptors. This unique property confirms that SmFtz-Fl may be involved in the development and differentiation of schistosome-specific structures. (C) 2004 Elsevier Inc. All rights reserved.