Identification of ligands and coligands for the ecdysone-regulated gene switch

The ecdysone-inducible gene switch is a useful tool for modulating gene exp ression in mammalian cells and transgenic animals. We have identified induc ers derived from plants as well as certain classes of insecticides that inc rease the versatility of this gene regulation system. Phytoecdysteroids sha re the favorable kinetics of steroids, but are inert in mammals. The gene r egulation properties of one of these ecdysteroids have been examined in cel l culture and in newly developed strains of ecdysone-system transgenic mice . Ponasterone A is a potent regulator of gene expression in cells and trans genic animals, enabling reporter genes to be turned on and off rapidly. A n umber of nonsteroidal insecticides have been identified that also activate the ecdysone system. Because the gene-controlling properties of the ecdyson e switch are based on a heterodimer composed of a modified ecdysone recepto r (VgEcR) and the retinoid X receptor (RXR), we have tested the effect of R XR ligands on the VgEcR/RXR complex. Used alone, RXR ligands display no act ivity on the ecdysone switch. However, when used in combination with a VgEc R ligand, RXR ligands dramatically enhance the absolute levels of induction . This property of the heterodimer has allowed the development of superindu cer combinations that increase the dynamic range of the system.