Receptor nomenclature NR0B1
Receptor code 4.10.1:OR:0:B1
Other names AHCH
Molecular information Hs: 470aa, P51843, chr. Xp211
Rn: 472aa, P70503, chr. Xq22
Mm: 472aa, Q61066, chr. X C12
DNA binding
   Structure Homodimer, heterodimer
   HRE core sequence DAX-1 lacks the conventional DNA-binding domain
Partners SF-1 (physical, functional): inhibition of SF-1-dependent transactivation by recruiting the nuclear receptor corepressor NCOR to SF-13,4; LRH-1 (physical, functional): inhibition of LRH-1-dependent transactivation4; ER (physical, functional): inhibition of ER-dependent transactivation5; AR (physical, functional): cellular localization, inhibition of ligand-dependent transcriptional activation, relocalization of AR in the cytoplasm and nucleus6,7; PR (physical, functional): inhibition of PR ligand-dependent transactivation via destabilization of the receptor dimers7
Corepressors NCOR1, NORR2, COPS23,7,8
Biologically important isoforms DAX-1α {Hs}: lacks the last 70aa of the DAX-1 protein; abundantly expressed in the adrenal gland, brain, kidney, ovary, and testis; can bind SF-1 and DNA but is unable to repress SF-1-mediated transactivation; may act as an antagonist to DAX-19,10
Tissue distribution Developmental: gonadal urogenital ridge, adrenal primordium, pituitary, diencephalon; adult: adrenal cortex, ovarian granulosa and theca cells, testicular Leydig and Sertoli cells, anterior pituitary gonadotrope cells, neurons of the ventromedial nucleus of the hypothalamus {Hs, Mm} [Northern blot, in situ hybridization, immunohistology]1,2,1113
Functional assays
Main target genes Repressed: DAX-1 {Hs, Mm, Rn},14 StAR {Hs, Mm, Rn}14
Mutant phenotype XY mice carrying extra copies of mouse DAX-1 as a transgene show delayed testis development when the gene is expressed at high levels but do not normally show sex reversal except when the transgene is introduced into mice strains carrying weak Sry alleles, confirming the notion that DAX-1 is responsible for DSS syndrome {Mm} [disruption caused by insertion of a vector]15; female mice lacking the DAX-1 receptor do not exhibit abnormal ovarian development or fertility; male mice lacking the DAX-1 receptor exhibit progressive degeneration of the testicular germinal epithelium, suggesting DAX-1 is essential for spermatogenesis; they also exhibit abnormalities in gonadotropin and testosterone production, further stressing the role of DAX-1 in steroidogenesis and HPA axis regulation {Mm} [disruption caused by insertion of a vector]15
Human disease HHG: all types of missense mutations in DAX-1 resulting in HHG localize in the ligand-binding domain; many mutations are frameshift or nonsense mutations that lead to a truncated DAX-1 protein16; DSS syndrome: due to a duplication of the DAX-1 gene and not to an alteration of the receptor2,17, 18; X-linked AHC: all types of missense mutations in DAX-1 resulting in AHC localize in the ligand-binding domain; many mutations are frameshift or nonsense mutations that lead to a truncated DAX-1 protein16,19,20
  • aa, amino acids; chr., chromosome; HRE, hormone response element; AR, androgen receptor; PR, progesterone receptor; HHG, hypogonadotropic hypogonadism; HPA, hypothalamo-pituitary-adrenal; AHC, adrenal hypoplasia congenita; DSS, dosage-sensitive sex reversal; StAR, steroidogenic acute regulatory protein

  • 1. Zanaria E, Muscatelli F, Bardoni B, Strom TM, Guioli S, Guo W, Lalli E, Moser C, Walker AP, McCabe ER, et al. (1994) An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature (Lond) 372: 635-641

  • 2. Swain A, Zanaria E, Hacker A, Lovell-Badge R, and Camerino G (1996) Mouse Dax1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus function. Nat Genet 12: 404-409

  • 3. Crawford PA, Dorn C, Sadovsky Y, and Milbrandt J (1998) Nuclear receptor DAX-1 recruits nuclear receptor corepressor N-CoR to steroidogenic factor 1. Mol Cell Biol 18: 2949-2956

  • 4. Suzuki T, Kasahara M, Yoshioka H, Morohashi K, and Umesono K (2003) LXXLL-related motifs in Dax-1 have target specificity for the orphan nuclear receptors Ad4BP/SF-1 and LRH-1. Mol Cell Biol 23: 238-249

  • 5. Zhang H, Thomsen JS, Johansson L, Gustafsson JA, and Treuter E (2000) DAX-1 functions as an LXXLL-containing corepressor for activated estrogen receptors. J Biol Chem 275: 39855-39859

  • 6. Holter E, Kotaja N, Makela S, Strauss L, Kietz S, Janne OA, Gustafsson JA, Palvimo JJ, and Treuter E (2002) Inhibition of androgen receptor (AR) function by the reproductive orphan nuclear receptor DAX-1. Mol Endocrinol 16: 515-528

  • 7. Agoulnik IU, Krause WC, Bingman WE, Rahman HT, Amrikachi M, Ayala GE, and Weigel NL (2003) Repressors of androgen and progesterone receptor action. J Biol Chem 278: 31136-31148

  • 8. Altincicek B, Tenbaum, Dressel U, Thormeyer D, Renkawitz R, and Baniahmad A (2000) Interaction of the corepressor Alien with DAX-1 is abrogated by mutations of DAX-1 involved in adrenal hypoplasia congenita. J Biol Chem 275: 7662-7667

  • 9. Ho J, Zhang YH, Huang BL, and McCabe ER (2004) NR0B1A: an alternatively spliced form of NR0B1. Mol Genet Metab 83: 330-336

  • 10. Hossain A, Li C, and Saunders GF (2004) Generation of two distinct functional isoforms of dosage-sensitive sex reversal-adrenal hypoplasia congenita-critical region on the X chromosome gene 1 (DAX-1) by alternative splicing. Mol Endocrinol 18: 1428-1437

  • 11. Ikeda Y, Swain A, Weber TJ, Hentges KE, Zanaria E, Lalli E, Tamai KT, Sassone-Corsi P, Lovell-Badge R, Camerino G, et al. (1996) Steroidogenic factor 1 and Dax-1 colocalize in multiple cell lineages: potential links in endocrine development. Mol Endocrinol 10: 1261-1272

  • 12. Parma P, Pailhoux E, Puissant C, and Cotinot C (1997) Porcine Dax-1 gene: isolation and expression during gonadal development. Mol Cell Endocrinol 135: 49-58

  • 13. Tamai IT, Monaco L, Alastalo TP, Lalli E, Parvinen M, and Sassone-Corsi P (1996) Hormonal and developmental regulation of DAX-1 expression in Sertoli cells. Mol Endocrinol 10: 1561-1569

  • 14. Zazopoulos E, Lalli E, Stocco DM, and Sassone-Corsi P (1997) DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis. Nature (Lond) 390: 311-315

  • 15. Yu RN, Ito M, Saunders TL, Camper SA, and Jameson JL (1998) Role of Ahch in gonadal development and gametogenesis. Nat Genet 20: 353-357

  • 16. Muscatelli F, Strom TM, Walker AP, Zanaria E, Recan D, Meindl A, Bardoni B, Guioli S, Zehetner G, Rabl W, et al. (1994) Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature (Lond) 372: 672-676

  • 17. Swain A and Lovell-Badge R (1997) A molecular approach to sex determination in mammals. Acta Paediatr Suppl 423: 46-49

  • 18. Swain A, Narvaez V, Burgoyne P, Camerino G, and Lovell-Badge R (1998) Dax1 antagonizes Sry action in mammalian sex determination. Nature (Lond) 391: 761-767

  • 19. Lalli E, Bardoni B, Zazopoulos E, Wurtz JM, Strom TM, Moras D, and Sassone-Corsi P (1997) A transcriptional silencing domain in DAX-1 whose mutation causes adrenal hypoplasia congenita. Mol Endocrinol 11: 1950-1960

  • 20. Zhang YH, Guo W, Wagner RL, Huang BL, McCabe L, Vilain E, Burris TP, Anyane-Yeboa K, Burghes AH, Chitayat D, et al. (1998) DAX1 mutations map to putative structural domains in a deduced three-dimensional model. Am J Hum Genet 62: 855-864