TRANSCRIPTIONAL ACTIVATION AND REPRESSION BY ROR-ALPHA, AN ORPHAN NUCLEAR RECEPTOR REQUIRED FOR CEREBELLAR DEVELOPMENT

Mutation of the orphan nuclear receptor ROR alpha results in a severe impairment of cerebellar development by unknown mechanisms. We have fo und that ROR alpha activates transcription from only a subset of sites to which it binds strongly as a monomer. ROR alpha also selectively b inds as a homodimer to a direct repeat of this monomer site with a 2-b p spacing between the AGGTCA sequences (RevDR2 site) and is a much mor e potent transcriptional activator on this site than on monomer sites or other direct repeats. To better understand the transcriptional regu latory functions of ROR alpha, we fused its C terminus to a heterologo us DNA-binding domain. Mutational analysis revealed that ROR alpha con tains both transcriptional activation and transcriptional repression d omains, with the repression domain being more active in some cell type s. The abilities of ROR alpha polypeptides to repress transcription co rrelate with their abilities to interact with the nuclear receptor cor epressors N-CoR and SMRT in vitro. However, the AF2 region of ROR alph a inhibits corepressor interaction on DNA, consistent with the lack of repression by the full-length receptor. Thus, transcriptional regulat ion by ROR alpha is complex and likely to be regulated in a cell type- and target gene-specific manner.