Molecular mechanisms of DAX1 action

Mol Genet Metab. Sep-Oct 2004;83(1-2):60-73. doi: 10.1016/j.ymgme.2004.07.018.


DAX1 (dosage sensitive sex reversal (DSS), adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1) encoded by the gene NR0B1, is an unusual orphan nuclear receptor that when mutated causes AHC with associated hypogonadotropic hypogonadism (HH), and when duplicated causes DSS. DAX1 expression has been shown in all regions of the hypothalamic-pituitary-adrenal-gonadal (HPAG) axis during development and in adult tissues, suggesting a critical role for DAX1 in the normal development and function of this axis. Steroidogenic factor 1 (SF1, NR5A1) knockout mice show similar developmental defects as AHC and HH patients, but paradoxically, DAX1 is a negative coregulator of SF1 transactivation. The function of DAX1 as an antagonist of SF1 in gonadal development is consistent with the fact that in humans, duplication of the region of the X chromosome containing DAX1 causes a similar phenotype as mutations in SF1. However, how disruption of DAX1 leads to adrenal, hypothalamic, and pituitary developmental defects similar to SF1 disruption remains to be clarified. The exact mechanism of DAX1 action in each of these tissues during adulthood and critical stages of development are not fully understood. Recent evidence suggests a broader functional role for DAX1 as a negative coregulator of estrogen receptor (ER, NR3A1-2), liver receptor homologue-1 (LRH-1, NR5A2), androgen receptor (AR, NR3C4), and progesterone receptor (PR, NR3C3), each by distinct repression mechanisms. DAX1 may have pleiotropic roles in addition to its function as a negative regulator of steroidogenesis during the development and adult function of the HPAG axis.

Publication types

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

MeSH terms

  • Animals
  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Female
  • Gene Expression Regulation, Developmental*
  • Homeodomain Proteins
  • Humans
  • Hypothalamo-Hypophyseal System / physiology*
  • Male
  • Mice
  • Ovary / growth & development
  • Ovary / physiology*
  • Pituitary-Adrenal System / physiology*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism
  • Receptors, Retinoic Acid / physiology*
  • Repressor Proteins / physiology*
  • Sex Determination Processes
  • Steroidogenic Factor 1
  • Testis / growth & development
  • Testis / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • NR0B1 protein, human
  • NR5A1 protein, human
  • NR5A2 protein, human
  • Nr0b1 protein, mouse
  • Receptors, Androgen
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Receptors, Retinoic Acid
  • Repressor Proteins
  • Steroidogenic Factor 1
  • Transcription Factors
  • steroidogenic factor 1, mouse