Nuclear Receptor DAX-1 Recruits Nuclear Receptor Corepressor N-CoR to Steroidogenic Factor 1

ABSTRACT

The orphan nuclear receptor steroidogenic factor 1 (SF-1) is a critical developmental regulator in the urogenital ridge, because mice targeted 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 whose tissue distribution overlaps that of SF-1. Naturally occurring loss-of-function mutations of the DAX-1 gene cause the human disorder X-linked adrenal hypoplasia congenita (AHC), which resembles the phenotype of SF-1-deficient mice. Paradoxically, however, DAX-1 represses the transcriptional activity of SF-1, and AHC mutants of DAX-1 lose repression function. To further investigate these findings, we characterized the interaction between SF-1 and DAX-1 and found that their interaction indeed occurs through a repressive domain within the carboxy terminus of SF-1. Furthermore, we demonstrate that DAX-1 recruits the nuclear receptor corepressor N-CoR to SF-1, whereas naturally occurring AHC mutations of DAX-1 permit the SF-1–DAX-1 interaction, but markedly diminish corepressor recruitment. Finally, the interaction between DAX-1 and N-CoR shares similarities with that of the nuclear receptor RevErb 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 receptors like SF-1, thereby extending the range of corepressor action.

ACKNOWLEDGMENTS

We thank M. Lazar, A. Hörlein, J. D. Chen, and P. Webb for providing plasmids used in this study. We thank S. Audrain for sequencing constructs. Finally, we thank J. Svaren and T. Wilson for critical review of the manuscript.

This work was supported by a grant from the National Cancer Institute (PO1-49712-07) (J.M.), an MSTP training grant (P.A.C.), and NIH grant HD-34110 (Y.S.).