NUCLEAR RECEPTOR DAX-1 RECRUITS NUCLEAR RECEPTOR COREPRESSOR N-COR TOSTEROIDOGENIC FACTOR-1

The orphan nuclear receptor steroidogenic factor 1 (SF-1) is a critica l developmental regulator in the urogenital ridge, because mice target ed for disruption of the SF-1 gene lack adrenal glands and gonads. SF- 1 was recently shown to interact with DAX-1, another orphan receptor w hose tissue distribution overlaps that of SF-1. Naturally occurring lo ss-of-function mutations of the DAX-1 gene cause the human disorder X- linked adrenal hypoplasia congenita (AHC), which resembles the phenoty pe of SF-1-deficient mice. Paradoxically, however, DAX-1 represses the transcriptional activity of SF-1, and AHC mutants of DAX-1 lose repre ssion function. To further investigate these findings, we characterize d the interaction between SF-1 and DAX-1 and found that their interact ion indeed occurs through a repressive domain within the carboxy termi nus of SF-1. Furthermore, we demonstrate that DAX-1 recruits the nucle ar receptor corepressor N-CoR to SF-1, whereas naturally occurring AHC mutations of DAX-1 permit the SF-1-DAX-1 interaction, but markedly di minish corepressor recruitment. Finally, the interaction between DAX-1 and N-CoR shares similarities with that of the nuclear receptor RevEr b and N-CoR, because the related corepressor SMRT was not efficiently recruited by DAX-1. Therefore, DAX-1 can serve as an adapter molecule that recruits nuclear receptor corepressors to DNA-bound nuclear recep tors like SF-1, thereby extending the range of corepressor action.