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Abstract
DAX-1 is an unusual member of the nuclear hormone receptor (NHR) superfamily. Lack of DAX-1-mediated silencing leads to adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Gene silencing through NHRs such as the thyroid hormone receptor (TR) is mediated by corepressors. We have previously characterized a novel corepressor, termed Alien, which interacts with TR and the ecdysone receptor but not with the retinoic acid receptors RAR or RXR. Here, we show that DAX-1 interacts with the corepressor Alien but not with the corepressor SMRT. This interaction is mediated by the DAX-1-silencing domain. Naturally occurring mutants of the DAX-1 gene fail to interact with 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 and with TR. We show that Alien exhibits different binding characteristics to DAX-1 and TR. Furthermore, Northern experiments demonstrate that Alien is expressed in the adrenal gland and testis in tissues where DAX-1 is specifically expressed. Interestingly, a novel adrenal gland-specific mRNA of Alien was discovered. Thus, the impairment of Alien binding seems to play an important role in the pathogenesis mediated by DAX-1 mutants.
Highlights
The gene superfamily of nuclear hormone receptors (NHRs)1 represents a large class of transcription factors including receptors for steroids, nonsteroids, and members for which no ligand has yet been identified, the so-called orphan receptors
All DAX-1 mutations found in patients with adrenal hypoplasia congenita have the common feature of an altered C terminus [27]
DAX-1 Interacts with the Corepressor Alien—We have recently characterized a novel corepressor for specific members of the NHR superfamily [13]
Summary
The gene superfamily of nuclear hormone receptors (NHRs)1 represents a large class of transcription factors including receptors for steroids, nonsteroids, and members for which no ligand has yet been identified, the so-called orphan receptors (for reviews, see Refs. 1 and 2). Based on sequence differences between the silencing domain of DAX-1 and that of NHRs, we analyzed the interaction of the corepressor Alien with DAX-1. Naturally occurring DAX-1 mutants, involved in adrenal hypoplasia congenita and the associated symptoms of hypogonadotropic hypogonadism, fail to interact with Alien and lack silencing function.
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