Functional analysis of retinoid Z receptor β, a brain-specific nuclear orphan receptor

The retinoid Z receptor β (RZRβ), an orphan receptor, is a member of the retinoic acid receptor (RAR)/thyroid hormone receptor (TR) subfamily of nuclear receptors. RZRβ exhibits a highly restricted brain-specific expression pattern. So far, no natural RZRβ 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 RZRβ to monomeric response elements containing the sequence AnnTAGGTCA, but RZRβ-mediated transactivation of reporter genes is only achieved with two properly spaced binding sites. We present evidence that RZRβ can function as a cell-type-specific transactivator. In neuronal cells, Gal-RZRβ 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 RZRβ and RARα are functionally interchangeable. However, in contrast to RAR and TR, the RZRβ 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 RZRβ is regulated by an interplay of different receptor domains with coactivators and corepressors.