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DAX1

Systematic Nomenclature: NR0B1

Family: 0B. DAX-like receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Selected 3D Structures
DNA Binding
Co-binding Partners
Main Co-regulators
Main Target Genes
Tissue Distribution
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
Gene Expression and Pathophysiology
Biologically Significant Variants
General Comments
References
Gene and Protein Information
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 470 Xp21.3-p21.2 NR0B1 nuclear receptor subfamily 0, group B, member 1 21
Mouse 472 X33.0cM Nr0b1 nuclear receptor subfamily 0, group B, member 1 18
Rat 472 Xq22 Nr0b1 nuclear receptor subfamily 0, group B, member 1
Previous and Unofficial Names
AHC
DSS
AHCH
DAX-1
dosage-sensitive sex reversal
adrenal hypoplasia congenital homolog (human)
adrenal hypoplasia, congenital homolog
nuclear receptor DAX-1
nuclear receptor subfamily 0 group B member 1
nuclear receptor subfamily 0, group B, member 1
AHX
Database Links
DrugBank Target 84 (Hs)
Ensembl ENSG00000169297 (Hs), ENSMUSG00000025056 (Mm), ENSRNOG00000003765 (Rn)
Entrez Gene 190 (Hs), 11614 (Mm), 58850 (Rn)
GeneCards NR0B1 (Hs)
GenitoUrinary Development Molecular Anatomy Project Nr0b1 (Mm)
Human Protein Reference Database 08362 (Hs)
InterPro P51843 (Hs), Q61066 (Mm), P70503 (Rn)
KEGG Gene hsa:190 (Hs), mmu:11614 (Mm), rno:58850 (Rn)
NURSA Receptor 0B1
OMIM 300473 (Hs)
Orphanet Gene ORPHA123902 (Hs)
PhosphoSitePlus P51843 (Hs), Q61066 (Mm), P70503 (Rn)
RefSeq Nucleotide NM_000475 (Hs), NM_007430 (Mm), NM_053317 (Rn)
RefSeq Protein NP_000466 (Hs), NP_031456 (Mm), NP_445769 (Rn)
TreeFam ENSG00000169297 (Hs), ENSMUSG00000025056 (Mm), ENSRNOG00000003765 (Rn)
UniProt P51843 (Hs), Q61066 (Mm), P70503 (Rn)
Wikipedia DAX1
Orphan nuclear receptors
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Structure of Dax-1:LRH-1 complex
PDB Id:  3F5C
Resolution:  3.0Å
Species:  Mouse
References:  14
Search for other structures on the PDB
Search by keyword: DAX1 Search by accession number: P51843, Q61066, P70503
Natural/Endogenous Ligand(s)
Comments: Orphan
DNA Binding
Structure:  Homodimer, Heterodimer
HRE core sequence: 
Response element:  Other - see comments
DNA Binding Comments
DAX1 strongly differs in its structural organization from other NRs. More specifically, it lacks the conventional DNA Binding Domain of other NRs. It was reported that DAX1 binds to DNA hairpin structure with no strong sequence specificity. Interestingly it was found recently that DAX1 is an RNA binding protein associated with polyribosomes that is shuttling between the cytoplasm and the nucleus. The N-terminal repeats as well as the LBD are directly implicated in the RNA recognition.
Co-binding Partners
Name Interaction Effect Reference
Steroidogenic factor 1 Physical, Functional Inhibition of SF-1 dependant transactivation by recruiting the nuclear receptor corepressor NCOR1 to SF-1 3,15
Liver receptor homolog-1 Physical, Functional Inhibition of LRH-1 dependent transactivation 15
Estrogen receptor-α Physical, Functional Inhibition of ER dependent transactivation 23
Androgen receptor Physical, Functional Cellular localization, DAX-1 also potently inhibits ligand-dependent transcriptional activation. DAX-1, known to shuttle between the cytoplasm and the nucleus, is capable of relocalizing AR in both cellular compartmentsR dimerization 1,6
Progesterone receptor Physical, Functional Inhibition of PR ligand dependent transactivation via destabilization of the receptor dimers 1
Main Co-regulators
Name Activity Specific Ligand dependent AF-2 dependent Comments References
NCOR1 Co-repressor No No - 4
NCOR2 Co-repressor - No - 1
COPS2 Co-repressor Yes No - 2
Main Target Genes
Name Species Effect Technique Comments References
NR0B1 Human Repressed NR0B1(DAX-1) is able to regulate its own expression by interacting with DNA hairpins present in its promoter. this has also been demonstrated in both the mouse and rat 22
STAR Human Repressed DAX1 interacts with DNA hairpin present in the StAR gene promoter and inhibit StAR expression. This inhibitory effect prevents steroid production as StAR is an essential protein for the transfer of cholesterol to the inner mitochondrial membrane, which is an essential step in steroid biosynthesis. 22
Tissue Distribution
adrenal cortex, ovarian granulosa and theca cells, testicular Leydig and Sertoli cells, anterior pituitary gonadotropes cells and in the neurons of the ventromedial nucleus of the hypothalamus...
Species:  Human
Technique:  Northern, In situ, Immunohistology, Other
References:  8,13,18-19,21
Tissue Distribution Comments
This pattern is reminiscent to the one of SF-1 and is consistent with a function of DAX1 in sex determination as well as in the control of the hypothalamus-pituitary-adrenal axis. In mice, DAX1 expression is first detected in the gonadal urogenital ridge at E10.5 and in the adrenal primordium at E12.5. In the pituitary the expression start at E14.5 whereas in the diencephalon it starts at E11.5. The first sexually divergent expression of DAX1 is seen in the gonad. In both case DAX1 expression is high at E12 but in the male (and not in the female) a rapid decline of expression follows. Similar findings have been observed in another mammal suggesting that this expression pattern is conserved. Similar patterns are seen in the mouse.
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0004728 abnormal efferent ductules of testis PMID: 11564714 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0002786 abnormal Leydig cell morphology PMID: 11564714  12538527 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0002118 abnormal lipid homeostasis PMID: 11564714 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0006420 abnormal peritubular myoid cell morphology PMID: 11564714 
Nr0b1tm1Lja Nr0b1tm1Lja/Y
C57BL/6JEi		 MGI:1352460  MP:0002211 abnormal primary sex determination PMID: 15944188 
Nr0b1tm1Lja Nr0b1tm1Lja/Y
involves: C57BL/6JEi * DBA/2J		 MGI:1352460  MP:0002211 abnormal primary sex determination PMID: 15944188 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0006304 abnormal seminiferous epithelium morphology PMID: 11564714  9843206 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0004109 abnormal Sertoli cell development PMID: 12538527 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0001156 abnormal spermatogenesis PMID: 9843206 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0006418 abnormal testis cord formation PMID: 12538527 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0001146 abnormal testis morphology PMID: 9843206 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0004806 absent germ cells PMID: 9843206 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0004901 decreased male germ cell number PMID: 9843206 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0006421 decreased number of peritubular myoid cells PMID: 12538527 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0004852 decreased testis weight PMID: 11564714  9843206 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0009257 dilated seminiferous tubules PMID: 11564714 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0006419 disorganized testis cords PMID: 12538527 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0006427 ectopic Leydig cells PMID: 11564714  12538527 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0006428 ectopic Sertoli cells PMID: 11564714 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0001152 Leydig cell hyperplasia PMID: 11564714  9843206 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0001925 male infertility PMID: 11564714  9843206 
Nr0b1tm1Lja Nr0b1tm1Lja/Y
involves: C57BL/6JEi * DBA/2J		 MGI:1352460  MP:0002996 ovotestis PMID: 15944188 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Nr0b1tm1.1Lja
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0009433 polyovular ovarian follicle PMID: 9843206 
Nr0b1tm1Lja Nr0b1tm1Lja/Y
C57BL/6JEi		 MGI:1352460  MP:0002995 primary sex reversal PMID: 15944188 
Nr0b1tm1Lja Nr0b1tm1Lja/Y
involves: C57BL/6JEi * DBA/2J		 MGI:1352460  MP:0002995 primary sex reversal PMID: 15944188 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0008297 retention of the x-zone PMID: 9843206 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0006417 rete testis obstruction PMID: 11564714 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0001154 seminiferous tubule degeneration PMID: 11564714  9843206 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0002776 Sertoli cell hyperplasia PMID: 11564714 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0001147 small testis PMID: 9843206 
Nr0b1tm1.1Lja Nr0b1tm1.1Lja/Y
involves: 129S1/Sv * 129X1/SvJ		 MGI:1352460  MP:0006262 testis tumor PMID: 11564714 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Dosage sensitive sex reversal (DSS) syndrome
OMIM:  300018
Orphanet:  242
Role:  DSS syndrome is due to a duplication of DAX1 gene and not to an alteration of the receptor.
References:  16-18
Mutations not determined
Disease:  Hypogonadotropic hypogonadism (HHG)
OMIM:  300473
Comments:  As for AHC, all types of missense mutation in DAX1 resulting in AHC localise in the ligand binding domain. Many mutations are frameshift or nonsense mutations that lead to truncated DAX1 protein
References:  11
Mutations not determined
Disease:  X-linked adrenal hypoplasia congenita (AHC)
OMIM:  202155, 300200
Orphanet:  95702
Role:  All types of missense mutation in DAX1 resulting in AHC localise in the ligand binding domain. Many mutations are frameshift or nonsense mutations that lead to truncated DAX1 protein
References:  10-11,24
Mutations not determined
Disease:  46,XY partial gonadal dysgenesis
Orphanet:  251510
References: 
Mutations not determined
Gene Expression and Pathophysiology
Disrupted sexual development
Tissue or cell type: 
Pathophysiology: 
Species:  Mouse
Technique:  Gene disruption by insertion of vector
References:  20
Gene Expression and Pathophysiology Comments
Since it was demonstrated as the gene responsible for the dosage sensitive sex reversal, which occurred when the DSS locus of chromosome Xp21 is duplicated, DAX1 has been used in transgenic experiments in order to test the effect of modification of the gene dosage. It was shown that XY mices carrying extra copies of mouse DAX1 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 was introduced in mice strains carrying weak Sry alleles. This has confirmed the notion that DAX1 was responsible for the DSS syndrome.In order to examined the function of DAX1 in both males and females a strain of mice carrying inactivated DAX1 alleles were generated. Strikingly, although DAX1 was first postulated to function in ovarian determination, the female mices do not exhibit abnormalities of ovarian development or fertility. In contrast, in males lack of DAX1 causes progressive degeneration of the testicular germinal epithelium suggesting that DAX1 is essential for spermatogenesis. In addition these animals exhibit abnormalities in gonadotropin and testosterone production, further stressing the role of DAX1 in steroidogenesis and hypothalamus-pituitary-adrenal axis regulation.
Biologically Significant Variants
DAX-1 alpha
Type:  Splice variant
Species:  Human
References:  5,7
Biologically Significant Variant Comments
This shorter isoform of DAX-1 lacks the last 70 aa of the previously described DAX-1 protein. It is abundantly expressed in the adrenal gland, brain, kidney, ovary, and testis. DAX-1alpha can bind to steroidogenic factor 1 and to DNA but is unable to repress steroidogenic factor 1-mediated transactivation. This isoform may act as an antagonist of DAX-1.
General Comments
For review see the following [9] and [12]

REFERENCES

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1. Agoulnik, IU; Krause, WC; Bingman, WE; Rahman, HT; Amrikachi, M; Ayala, GE; Weigel, NL. (2003) Repressors of androgen and progesterone receptor action. J. Biol. Chem., 278 (33): 31136-48. [PMID:12771131]

2. Altincicek, B; Tenbaum, SP; Dressel, U; Thormeyer, D; Renkawitz, R; 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 (11): 7662-7. [PMID:10713076]

3. Crawford, PA; Dorn, C; Sadovsky, Y; Milbrandt, J. (1998) Nuclear receptor DAX-1 recruits nuclear receptor corepressor N-CoR to steroidogenic factor 1. Mol. Cell. Biol., 18 (5): 2949-56. [PMID:9566914]

4. Crowston, J. G., Lindsey, J. D., Morris, C. A., Wheeler, L., Medeiros, F. A. and Weinreb, R. N. (2005) Effect of bimatoprost on intraocular pressure in prostaglandin FP receptor knockout mice. Invest Ophthalmol Vis Sci, 46: 4571-4577. [PMID:16303950]

5. Ho, J; Zhang, YH; Huang, BL; McCabe, ER. (2004) NR0B1A: an alternatively spliced form of NR0B1. Mol. Genet. Metab., 83 (4): 330-6. [PMID:15589120]

6. Holter, E; Kotaja, N; Mäkela, S; Strauss, L; Kietz, S; Jänne, OA; Gustafsson, JA; Palvimo, JJ; Treuter, E. (2002) Inhibition of androgen receptor (AR) function by the reproductive orphan nuclear receptor DAX-1. Mol. Endocrinol., 16 (3): 515-28. [PMID:11875111]

7. Hossain, A; Li, C; 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 (6): 1428-37. [PMID:15044589]

8. Ikeda, Y; Swain, A; Weber, TJ; Hentges, KE; Zanaria, E; Lalli, E; Tamai, KT; Sassone-Corsi, P; Lovell-Badge, R; Camerino, G; Parker, KL. (1996) Steroidogenic factor 1 and Dax-1 colocalize in multiple cell lineages: potential links in endocrine development. Mol. Endocrinol., 10 (10): 1261-72. [PMID:9121493]

9. Iyer, AK; McCabe, ER. (2004) Molecular mechanisms of DAX1 action. Mol. Genet. Metab., 83 (1-2): 60-73. [PMID:15464421]

10. Lalli, E; Bardoni, B; Zazopoulos, E; Wurtz, JM; Strom, TM; Moras, D; Sassone-Corsi, P. (1997) A transcriptional silencing domain in DAX-1 whose mutation causes adrenal hypoplasia congenita. Mol. Endocrinol., 11 (13): 1950-60. [PMID:9415399]

11. Muscatelli, F; Strom, TM; Walker, AP; Zanaria, E; Récan, D; Meindl, A; Bardoni, B; Guioli, S; Zehetner, G; Rabl, W. (1994) Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature, 372 (6507): 672-6. [PMID:7990958]

12. Niakan, KK; McCabe, ER. (2005) DAX1 origin, function, and novel role. Mol. Genet. Metab., 86 (1-2): 70-83. [PMID:16146703]

13. Parma, P; Pailhoux, E; Puissant, C; Cotinot, C. (1997) Porcine Dax-1 gene: isolation and expression during gonadal development. Mol. Cell. Endocrinol., 135 (1): 49-58. [PMID:9453240]

14. Sablin, EP; Woods, A; Krylova, IN; Hwang, P; Ingraham, HA; Fletterick, RJ. (2008) The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1. Proc. Natl. Acad. Sci. U.S.A., 105 (47): 18390-5. [PMID:19015525]

15. Suzuki, T; Kasahara, M; Yoshioka, H; Morohashi, K; 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 (1): 238-49. [PMID:12482977]

16. Swain, A; Lovell-Badge, R. (1997) A molecular approach to sex determination in mammals. Acta Paediatr Suppl, 423: 46-9. [PMID:9401538]

17. Swain, A; Narvaez, V; Burgoyne, P; Camerino, G; Lovell-Badge, R. (1998) Dax1 antagonizes Sry action in mammalian sex determination. Nature, 391 (6669): 761-7. [PMID:9486644]

18. Swain, A; Zanaria, E; Hacker, A; Lovell-Badge, R; 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 (4): 404-9. [PMID:8630494]

19. Tamai, KT; Monaco, L; Alastalo, TP; Lalli, E; Parvinen, M; Sassone-Corsi, P. (1996) Hormonal and developmental regulation of DAX-1 expression in Sertoli cells. Mol. Endocrinol., 10 (12): 1561-9. [PMID:8961266]

20. Yu, RN; Ito, M; Saunders, TL; Camper, SA; Jameson, JL. (1998) Role of Ahch in gonadal development and gametogenesis. Nat. Genet., 20 (4): 353-7. [PMID:9843206]

21. Zanaria, E; Muscatelli, F; Bardoni, B; Strom, TM; Guioli, S; Guo, W; Lalli, E; Moser, C; Walker, AP; McCabe, ER. (1994) An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature, 372 (6507): 635-41. [PMID:7990953]

22. Zazopoulos, E; Lalli, E; Stocco, DM; Sassone-Corsi, P. (1997) DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis. Nature, 390 (6657): 311-5. [PMID:9384387]

23. Zhang, H; Thomsen, JS; Johansson, L; Gustafsson, JA; Treuter, E. (2000) DAX-1 functions as an LXXLL-containing corepressor for activated estrogen receptors. J. Biol. Chem., 275 (51): 39855-9. [PMID:11053406]

24. Zhang, YH; Guo, W; Wagner, RL; Huang, BL; McCabe, L; Vilain, E; Burris, TP; Anyane-Yeboa, K; Burghes, AH; Chitayat, D; Chudley, AE; Genel, M; Gertner, JM; Klingensmith, GJ; Levine, SN; Nakamoto, J; New, MI; Pagon, RA; Pappas, JG; Quigley, CA; Rosenthal, IM; Baxter, JD; Fletterick, RJ; McCabe, ER. (1998) DAX1 mutations map to putative structural domains in a deduced three-dimensional model. Am. J. Hum. Genet., 62 (4): 855-64. [PMID:9529340]

To cite this database page, please use the following:

0B. DAX-like receptors: DAX1. Last modified on 07/01/2013. Accessed on 18/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=635.


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