Feedback-inducible nuclear-receptor-driven reporter gene expression in transgenic mice

Understanding nuclear receptor signaling in vivo would be facilitated by an efficient methodology to determine where a nuclear receptor is active. Her ein, we present a feedback-inducible expression system in transgenic mice t o detect activated nuclear receptor effector proteins by using an inducible reporter gene. With this approach, reporter gene induction is not limited to a particular tissue, and, thus, this approach provides the opportunity f or whole-animal screens. Furthermore, the effector and reporter genes are c ombined to generate a single strain of transgenic mice, which enables direc t and rapid analysis of the offspring. The system was applied to localize s ites where the retinoic acid receptor ligand-binding domain is activated in vivo. The results identify previously discovered sources of retinoids in t he embryo and indicate the existence of previously undiscovered regions of retinoic acid receptor signaling in vivo. Notably, the feedback-inducible n uclear-receptor-driven assay, combined with an independent in vitro assay, provides evidence for a site of retinoid synthesis in the isthmic mesenchym e. These data illustrate the potential of feedback-inducible nuclear-recept or-driven analyses for assessing in vivo activation patterns of nuclear rec eptors and for analyzing pharmacological properties of natural and syntheti c ligands of potential therapeutic value.