Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression

Cell. 1998 May 1;93(3):445-54. doi: 10.1016/s0092-8674(00)81172-1.

Abstract

Products of steroidogenic factor 1 (SF-1) and Wilms' tumor 1 (WT1) genes are essential for mammalian gonadogenesis prior to sexual differentiation. In males, SF-1 participates in sexual development by regulating expression of the polypeptide hormone Müllerian inhibiting substance (MIS). Here, we show that WT1 -KTS isoforms associate and synergize with SF-1 to promote MIS expression. In contrast, WT1 missense mutations, associated with male pseudohermaphroditism in Denys-Drash syndrome, fail to synergize with SF-1. Additionally, the X-linked, candidate dosage-sensitive sex-reversal gene, Dax-1, antagonizes synergy between SF-1 and WT1, most likely through a direct interaction with SF-1. We propose that WT1 and Dax-1 functionally oppose each other in testis development by modulating SF-1-mediated transactivation.

Publication types

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

MeSH terms

  • Animals
  • Anti-Mullerian Hormone
  • Cell Line
  • DAX-1 Orphan Nuclear Receptor
  • DNA / metabolism
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Disorders of Sex Development / genetics
  • Female
  • Fushi Tarazu Transcription Factors
  • Gene Expression Regulation, Developmental / genetics
  • Genes, Wilms Tumor / physiology
  • Glycoproteins*
  • Growth Inhibitors / genetics*
  • Homeodomain Proteins
  • Humans
  • Male
  • Models, Genetic
  • Mutation
  • Organ Specificity
  • Ovary / chemistry
  • Ovary / embryology
  • Placenta / cytology
  • RNA, Messenger / analysis
  • Rats
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism
  • Receptors, Retinoic Acid / physiology*
  • Repressor Proteins*
  • Sex Determination Processes
  • Steroidogenic Factor 1
  • Testicular Hormones / genetics*
  • Testis / chemistry
  • Testis / embryology
  • Transcription Factors / analysis
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Transcriptional Activation / genetics*
  • WT1 Proteins

Substances

  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins
  • Fushi Tarazu Transcription Factors
  • Glycoproteins
  • Growth Inhibitors
  • Homeodomain Proteins
  • NR0B1 protein, human
  • NR5A1 protein, human
  • Nr0b1 protein, rat
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Repressor Proteins
  • Steroidogenic Factor 1
  • Testicular Hormones
  • Transcription Factors
  • WT1 Proteins
  • steroidogenic factor 1, rat
  • Anti-Mullerian Hormone
  • DNA