Functional Analysis of Retinoid Z Receptor $\beta $, a Brain-Specific Nuclear Orphan Receptor

The retinoid Z receptor $\beta $ (RZR$\beta $), an orphan receptor, is a member of the retinoic acid receptor (RAR)/thyroid hormone receptor (TR) subfamily of nuclear receptors. RZR$\beta $ exhibits a highly restricted brain-specific expression pattern. So far, no natural RZR$\beta $ target gene has been identified and the physiological role of the receptor in transcriptional regulation remains to be elucidated. Electrophoretic mobility shift assays reveal binding of RZR$\beta $ to monomeric response elements containing the sequence AnnTAGGTCA, but RZR$\beta $-mediated transactivation of reporter genes is only achieved with two properly spaced binding sites. We present evidence that RZR$\beta $ can function as a cell-type-specific transactivator. In neuronal cells, Gal-RZR$\beta $ fusion proteins function as potent transcriptional activators, whereas no transactivation can be observed in nonneuronal cells. Mutational analyses demonstrate that the activation domain (AF-2) of RZR$\beta $ and RAR$\alpha $ are functionally interchangeable. However, in contrast to RAR and TR, the RZR$\beta $ AF-2 cannot function autonomously as a transactivation domain. Furthermore, our data define a novel repressor function for the C-terminal part of the putative ligand binding domain. We propose that the transcriptional activity of RZR$\beta $ is regulated by an interplay of different receptor domains with coactivators and corepressors.