Although an increasing number of nuclear orphan receptors have recently been identified, the number of known naturally occurring genes that are directly regulated by orphan receptors is still small. We have shown previously that the gene encoding the neuropeptide oxytocin (OT) is negatively regulated by the orphan receptors chicken ovalbumin upstream transcription factor I (COUP-TFI) and II. Here we show that the mouse OT gene promoter is activated by RORalpha, a representative of the ROR/RZR orphan receptor subfamily. Using promoter/chloramphenicol acetyltransferase reporter constructs in heterologous transfection assays, we determined that RORalpha action induces a <6-fold increase in promoter activity. By 5' and 3' deletion analysis, DNase footprint analysis and electrophoretic mobility shift assays, we found that RORalpha action is mediated by two 14 bp regions centered at 160 and 180 nucleotides upstream of the transcriptional initiation site. Both sites contain significant sequence identities with an established ROR recognition sequence. Mutations in either or both of these sites reduce significantly RORalpha-induced activation of the OT promoter. In view of the strong transcriptional activation exerted by RORalpha on the OT gene promoter and the widespread distribution of different members of the ROR/RZR family, interactions between ROR/RZR isoforms and the OT gene may form part of the multifactorial regulatory mechanisms that control OT gene expression in different tissues.

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