Interaction between Dax-1 and steroidogenic factor-1 in vivo: increased adrenal responsiveness to ACTH in the absence of Dax-1

Abstract

Two nuclear receptors, dosage-sensitive sex reversal adrenal hypoplasia congenita, critical region on the X chromosome gene-1 (Dax-1) and steroidogenic factor-1 (SF-1), are required for adrenal development and function. In vitro assays suggest that Dax-1 represses SF-1 mediated transcription. In this study, we generated SF-1(+/-): Dax-1(-/Y) mice to examine the role of Dax-1 in SF-1-dependent steroidogenesis in vivo. While the SF-1 expression was impaired in SF-1(+/-) mice, there was no change in Dax-1 expression in SF-1(+/-) mice and no change in SF-1 expression in Dax-1(-/Y) mice. SF-1(+/-) mice had small adrenal glands with adrenal hypoplasia and cellular hypertrophy. The loss of Dax-1 in SF-1(+/-): Dax-1(-/Y) mice reversed the decreased adrenal weight and histological abnormalities observed in SF-1(+/-) mice. SF-1(+/-) mice had elevated ACTH and the lowest corticosterone following restraint stress. In contrast, Dax-1(-/Y) mice had elevated corticosterone and decreased ACTH. Adrenal responsiveness (ACTH/corticosterone) was highest in Dax-1(-/Y) mice, intermediate in WT and SF-1(+/-): Dax-1(-/Y) mice, and lowest in SF-1(+/-) mice. In accordance with these findings, ACTH stimulation testing resulted in the highest levels of corticosterone in the Dax-1(-/Y) mice. Protein levels of P450c21 and the ACTH receptor were increased in Dax-1(-/Y) mice and intermediate in SF-1(+/-): Dax-1(-/Y) mice following chronic food deprivation. These results are consistent with a model in which Dax-1 functions to inhibit SF-1-mediated steroidogenesis in vivo.