The fushi tarazu factor 1 (FTZ-F1) nuclear receptor subfamily comprises orphan receptors with crucial roles in development and sexual differentiation in vertebrates and invertebrates. We describe the structure and functional properties of an FTZ-F1 from the platyhelminth parasite of humans, Schistosoma mansoni, the first receptor from this family to be characterized in a Lophotrochozoan. It contains a well conserved DNA-binding domain (55-63% identity to other family members) and a poorly conserved ligandbinding domain (20% identity to that of zebrafish FF1a). However, both the ligand domain signature sequence and the activation function 2-activation domain (AF2-AD) are perfectly conserved. Phylogenetic analysis confirmed that SmFTZ-F1 is a member of nuclear receptor subfamily 5, but that it clustered with the Drosophila receptor DHR39 and has consequently been named NR5B1. The gene showed a complex structure with 10 exons and an overall size of 18.4 kb. Two major transcripts were detected, involving alternative promoter usage and splicing of the two 5¢ exons, but which encoded identical proteins. SmFTZ-F1 mRNA is expressed at all life-cycle stages with the highest amounts in the larval forms (miracidia, sporocysts and cercariae). However, expression of the protein showed a different pattern; low in miracidia and higher in adult male worms. The protein bound the same monomeric response element as mammalian SF-1 (SF-1 response element, SFRE) and competition experiments with mutant SFREs showed that its specificity was identical. Moreover, SmFTZ-F1 transactivated reporter gene transcription from SFRE similarly to SF-1. This functional conservation argues for a conserved biological role of the FTZ-F1 nuclear receptor family throughout the metazoa.Keywords: platyhelminth; development; orphan receptor; phylogeny; DNA-binding.The FTZ-F1 gene subfamily encodes orphan nuclear receptors and appears to be present in all metazoan phyla [1]. The first member of the subfamily, FTZ-F1a, was isolated from Drosophila melanogaster [2,3] and was identified both as a transcriptional regulator and cofactor [4,5] of the homeodomain protein fushi tarazu (FTZ), a segmentation gene of the pair-rule class responsible for the formation of alternative segmental units in the D. melanogaster embryo [6]. FTZ-F1a is expressed in early embryos, concomitant with FTZ expression. A second isoform, FTZ-F1b, encoded by the same gene [7], is detectable in late-stage embryos through to adults, when FTZ expression is absent, and regulates genes associated with ecdysis and metamorphosis [8]. In the nematode Caenorhabditis elegans, nhr-25, the homologue of FTZ-F1, is required for epidermal and somatic gonad development and also participates in the regulation of moulting [9,10]. In vertebrates, an FTZ-F1 orthologue was first identified as a steroidogenic factor (Ad4BP/SF-1) present in the adrenal gland and able to bind to proximal promoter regions of cytochrome P450 steroid hydroxylase genes (reviewed in [11]). Further studies performed to identify the t...