title: 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.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109-0678, USA.
authors.forename: Poda Suresh
authors.initials: PS
authors.lastname: Babu
authors.forename: David L
authors.initials: DL
authors.lastname: Bavers
authors.forename: Felix
authors.initials: F
authors.lastname: Beuschlein
authors.forename: Sonalee
authors.initials: S
authors.lastname: Shah
authors.forename: Baxter
authors.initials: B
authors.lastname: Jeffs
authors.forename: J Larry
authors.initials: JL
authors.lastname: Jameson
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hammer
mesh_terms: D000302:Adrenal Cortex / Q000378:metabolism / Q000502:physiology; D000311:Adrenal Glands / Q000254:growth & development / Q000502:physiology*; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000502:physiology*; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D003345:Corticosterone / Q000097:blood; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D005260:Female; D005508:Food Deprivation / Q000502:physiology; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D012097:Repressor Proteins; D012149:Restraint, Physical; D054339:Steroidogenic Factor 1; D013315:Stress, Psychological / Q000503:physiopathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; C539966:Nr0b1 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone