The murine Dax-1 promoter is stimulated by SF-1 (steroidogenic factor-1) and inhibited by COUP-TF (chicken ovalbumin upstream promoter-transcription factor) via a composite nuclear receptor-regulatory element

Mol Endocrinol. 1998 Jul;12(7):1010-22. doi: 10.1210/mend.12.7.0131.


The Dax-1 gene encodes a protein that is structurally related to members of the orphan nuclear receptor superfamily. Dax-1 is coexpressed with another orphan nuclear receptor, steroidogenic factor-1 (SF-1), in the adrenal, gonads, hypothalamus, and pituitary gland. Mutations in Dax-1 cause adrenal hypoplasia congenita, a disorder that is characterized by adrenal insufficiency and hypogonadotropic hypogonadism. These developmental and endocrine abnormalities are similar to those caused by disruption of the murine Ftz-F1 gene (which encodes SF-1), suggesting that these nuclear receptors act along the same developmental cascade. Cloning of the murine Dax-1 gene revealed a candidate SF-1-binding site in the Dax-1 promoter. In transient expression assays in SF-1-deficient JEG-3 cells, SF-1 stimulated expression of the Dax-1 promoter. However, deletion or mutation of the consensus SF-1-binding site did not eliminate SF-1 stimulation. Further analyses revealed the presence of a cryptic SF-1 site that creates an imperfect direct repeat of the SF-1 element. When linked to the minimal thymidine kinase promoter, each of the isolated SF-1 sites was sufficient to mediate transcriptional regulation by SF-1. Mutation of both SF-1 sites eliminated SF-1 binding and stimulation of the Dax-1 promoter. Unexpectedly, mutation of either half of the composite SF-1 sites increased basal activity in JEG-3 cells, suggesting interaction of a repressor protein. Gel shift analyses of the composite response element revealed an additional complex that was not supershifted by SF-1 antibodies. This complex was eliminated by mutation of either half-site, and it was supershifted by antibodies against chicken ovalbumin upstream promoter-transcription factor (COUP-TF). We propose that Dax-1 is stimulated by SF-1, and that SF-1 and COUP-TF provide antagonistic pathways that converge upon a common regulatory site.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites
  • COUP Transcription Factor I
  • Cell Line
  • Cell Nucleus / metabolism*
  • Choriocarcinoma / metabolism
  • DAX-1 Orphan Nuclear Receptor
  • DNA / chemistry
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / pharmacology*
  • DNA-Binding Proteins / physiology*
  • Female
  • Fushi Tarazu Transcription Factors
  • Homeodomain Proteins
  • Humans
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Placenta / metabolism
  • Promoter Regions, Genetic*
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid / genetics*
  • Regulatory Sequences, Nucleic Acid*
  • Repressor Proteins*
  • Steroidogenic Factor 1
  • Thymidine Kinase / genetics
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription Factors / pharmacology*
  • Transcription Factors / physiology*
  • Tumor Cells, Cultured


  • COUP Transcription Factor I
  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins
  • Fushi Tarazu Transcription Factors
  • Homeodomain Proteins
  • NR0B1 protein, human
  • NR2F1 protein, human
  • NR5A1 protein, human
  • Nr0b1 protein, mouse
  • Nr2f1 protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Repressor Proteins
  • Steroidogenic Factor 1
  • Transcription Factors
  • steroidogenic factor 1, mouse
  • DNA
  • Thymidine Kinase