Interaction of the corepressor Alien with DAX-1 is abrogated by mutations of DAX-1 involved in adrenal hypoplasia congenita

DAX-1 is an unusual member of the nuclear hormone receptor (NHR) superfamil y. Lack of DAX-1-mediated silencing leads to adrenal hypoplasia congenita a nd hypogonadotropic hypogonadism, Gene silencing through NHRs such as the t hyroid hormone receptor (TR) is mediated by corepressors. We have previousl y characterized a novel corepressor, termed Alien, which interacts with TR and the ecdysone receptor but not with the retinoic acid receptors RAR or R XR. Here, we show that DAX-1 interacts with the corepressor Alien but not w ith the corepressor SMRT. This interaction is mediated by the DAX-1-silenci ng domain. Naturally occurring mutants of the DAX-1 gene fail to interact w ith Alien and have lost silencing function. Because the silencing domain of DAX-1 is unusual for NHRs, we mapped the interaction of Alien with DAX-1 a nd with TR. We show that Alien exhibits different binding characteristics t o DAX-1 and TR. Furthermore, Northern experiments demonstrate that Alien is expressed in the adrenal gland and testis in tissues where DAX-1 is specif ically expressed. Interestingly, a novel adrenal gland-specific mRNA of Ali en was discovered. Thus, the impairment of Alien binding seems to play an i mportant role in the pathogenesis mediated by DAX-1 mutants.