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Interaction Between Dax-1 and Steroidogenic Factor-1 in Vivo: Increased Adrenal Responsiveness to ACTH in the Absence of Dax-1

Division of Endocrinology (B.J., J.L.J.), Metabolism and Molecular Medicine, Northwestern University Medical School, Chicago, Illinois 60611; and Internal Medicine and Physiology (P.S.B., D.L.B., F.B., S.S., G.D.H.), University of Michigan, Ann Arbor, Michigan 48109-0678

Address all correspondence and requests for reprints to: Gary D. Hammer, M.D., Ph.D., Assistant Professor, Internal Medicine and Physiology, University of Michigan 5560A MSRB II, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-0678. E-mail: ghammer{at}umich.edu

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.

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