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Gene Review

Nr5a1  -  nuclear receptor subfamily 5, group A,...

Mus musculus

Synonyms: Ad4BP, Adrenal 4-binding protein, ELP, ELP-3, Embryonal LTR-binding protein, ...
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Disease relevance of Nr5a1


Psychiatry related information on Nr5a1


High impact information on Nr5a1

  • Male mice homozygous for the mutant SF1-binding site correctly initiated Mis transcription in fetal testes, although at significantly reduced levels [7].
  • Studies in adrenocortical cells have implicated the orphan nuclear receptor SF-1 in the gene regulation of the steroid hydroxylases [8].
  • Despite normal survival in utero, all Ftz-F1 null animals died by postnatal day 8; these animals lacked adrenal glands and gonads and were severely deficient in corticosterone, supporting adrenocortical insufficiency as the probable cause of death [8].
  • Male and female Ftz-F1 null mice had female internal genitalia, despite complete gonadal agenesis [8].
  • One mechanism to account for the negative role of Tpit in differentiation may be trans-repression between Tpit and the gonadotroph-restricted factor SF1 [9].

Chemical compound and disease context of Nr5a1


Biological context of Nr5a1


Anatomical context of Nr5a1

  • Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side-chain-cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids [17].
  • Within the adrenal cortex, ACTH-dependent transcriptional responses, including transcriptional activation of several key steroidogenic enzymes within the steroid biosynthetic pathway, are largely dependent upon SF-1 action [18].
  • We find that its major promoter resides at exon 2 in the pituitary gonadotrope alphaT3-1 cell line and that there is a nuclear hormone receptor binding site in this region, to which SF-1 can bind and regulate nNOS transcription [16].
  • The testes of adult gonad-specific SF-1 KO mice remained at the level of the bladder and were markedly hypoplastic, due at least partly to impaired spermatogenesis [1].
  • In the present study, gel shift analysis using nuclear extracts of either Y1 cells or bovine luteal cells demonstrated that the sequence between -57 and -32 bp bound SF-1 [19].

Associations of Nr5a1 with chemical compounds

  • Finally, SF-1 interacted with a previously defined promoter element in the glycoprotein hormone alpha-subunit gene, providing a possible mechanism for the impaired gonadotropin expression in Ftz-F1-disrupted mice [20].
  • These results confirm that SF-1 is an important regulator of adrenal and gonadal development, but its regulation of steroid hydroxylase expression in vivo remains to be established [17].
  • While serum levels of corticosterone in SF-1-deficient mice were diminished, levels of adrenocorticotropic hormone (ACTH) were elevated, consistent with intact pituitary corticotrophs [17].
  • A dominant negative of SF-1, in which the transactivation (AF-2) domain of SF-1 was deleted, inhibits nNOS exon 2 promoter activity [16].
  • Using transgenic mice, we previously delimited the regulatory DNA sequences necessary for expression in both organs and identified by cell transfections, a cryptic steroidogenic factor-1 (SF-1) response element (SFRE) at -102 that overlaps a proximal androgen-responsive element [21].

Physical interactions of Nr5a1

  • We have previously demonstrated the ability of SF-1 to bind to and transactivate the rat LHbeta gene promoter acting at a consensus gonadotrope-specific element (GSE) located at position -127 [15].
  • Our results demonstrate that ACTH-dependent signaling cascades modulate the temporal dynamics of SF-1-dependent complex assembly on the Mc2r promoter [18].
  • We found that SF-1 is able to bind to two sites in the Vanin-1 promoter, whereas SOX9 can bind to a single interposed site defined by DNA footprinting [22].
  • Nuclear factor Y and steroidogenic factor 1 physically and functionally interact to contribute to cell-specific expression of the mouse Follicle-stimulating hormone-beta gene [23].
  • DAX-1 especially inhibited binding of SF-1 to the binding motifs locating at positions -64 to -56 and -115 to -107, whereas no decrease was seen in the expression of SF-1 [24].

Regulatory relationships of Nr5a1


Other interactions of Nr5a1

  • Although other Egr proteins are expressed in LbetaT2 cells and are capable of interacting with SF-1, GnRH stimulation of Egr-1 was the most robust [25].
  • We conclude that the synergy between Egr-1 and SF-1 is essential for GnRH stimulation of the LHbeta gene and plays a central role in the dynamic regulation of LHbeta expression [25].
  • The absence of a bona fide endogenous eukaryotic ligand for SF-1 suggests that signaling pathway activation downstream of the melanocortin 2 receptor (Mc2r) modulates this transcriptional response [18].
  • Aromatase expression in testis occurs via transcription from promoter II, and requires the presence of a nuclear receptor half-site that binds the orphan receptor steroidogenic factor-1 [SF-1 (nuclear receptor 5A1)] to mediate basal and (in part) cAMP-induced transcription [27].
  • Surprisingly, SRC-1 deficiency did not alter baseline HPA axis function or the acute rise in corticosterone after ACTH administration and failed to exacerbate adrenocortical dysfunction in SF-1+/- mice [28].

Analytical, diagnostic and therapeutic context of Nr5a1


  1. Cell-specific knockout of steroidogenic factor 1 reveals its essential roles in gonadal function. Jeyasuria, P., Ikeda, Y., Jamin, S.P., Zhao, L., De Rooij, D.G., Themmen, A.P., Behringer, R.R., Parker, K.L. Mol. Endocrinol. (2004) [Pubmed]
  2. Steroidogenic factor 1 and Dax-1 colocalize in multiple cell lineages: potential links in endocrine development. Ikeda, Y., Swain, A., Weber, T.J., Hentges, K.E., Zanaria, E., Lalli, E., Tamai, K.T., Sassone-Corsi, P., Lovell-Badge, R., Camerino, G., Parker, K.L. Mol. Endocrinol. (1996) [Pubmed]
  3. Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor I. Lala, D.S., Rice, D.A., Parker, K.L. Mol. Endocrinol. (1992) [Pubmed]
  4. Interaction between Dax-1 and steroidogenic factor-1 in vivo: increased adrenal responsiveness to ACTH in the absence of Dax-1. Babu, P.S., Bavers, D.L., Beuschlein, F., Shah, S., Jeffs, B., Jameson, J.L., Hammer, G.D. Endocrinology (2002) [Pubmed]
  5. Haploinsufficiency of steroidogenic factor-1 in mice disrupts adrenal development leading to an impaired stress response. Bland, M.L., Jamieson, C.A., Akana, S.F., Bornstein, S.R., Eisenhofer, G., Dallman, M.F., Ingraham, H.A. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  6. Tissue-specific knockouts of steroidogenic factor 1. Zhao, L., Bakke, M., Hanley, N.A., Majdic, G., Stallings, N.R., Jeyasuria, P., Parker, K.L. Mol. Cell. Endocrinol. (2004) [Pubmed]
  7. Targeted mutagenesis of the endogenous mouse Mis gene promoter: in vivo definition of genetic pathways of vertebrate sexual development. Arango, N.A., Lovell-Badge, R., Behringer, R.R. Cell (1999) [Pubmed]
  8. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Luo, X., Ikeda, Y., Parker, K.L. Cell (1994) [Pubmed]
  9. Tpit determines alternate fates during pituitary cell differentiation. Pulichino, A.M., Vallette-Kasic, S., Tsai, J.P., Couture, C., Gauthier, Y., Drouin, J. Genes Dev. (2003) [Pubmed]
  10. Hypomorphic phenotype in mice with pituitary-specific knockout of steroidogenic factor 1. Zhao, L., Bakke, M., Krimkevich, Y., Cushman, L.J., Parlow, A.F., Camper, S.A., Parker, K.L. Genesis (2001) [Pubmed]
  11. Synergy of SF1 and RAR in activation of Oct-3/4 promoter. Barnea, E., Bergman, Y. J. Biol. Chem. (2000) [Pubmed]
  12. Mouse Polycomb M33 is required for splenic vascular and adrenal gland formation through regulating Ad4BP/SF1 expression. Katoh-Fukui, Y., Owaki, A., Toyama, Y., Kusaka, M., Shinohara, Y., Maekawa, M., Toshimori, K., Morohashi, K. Blood (2005) [Pubmed]
  13. Development of a transgenic green fluorescent protein lineage marker for steroidogenic factor 1. Stallings, N.R., Hanley, N.A., Majdic, G., Zhao, L., Bakke, M., Parker, K.L. Mol. Endocrinol. (2002) [Pubmed]
  14. LXXLL-related motifs in Dax-1 have target specificity for the orphan nuclear receptors Ad4BP/SF-1 and LRH-1. Suzuki, T., Kasahara, M., Yoshioka, H., Morohashi, K., Umesono, K. Mol. Cell. Biol. (2003) [Pubmed]
  15. Steroidogenic factor-1 and early growth response protein 1 act through two composite DNA binding sites to regulate luteinizing hormone beta-subunit gene expression. Halvorson, L.M., Ito, M., Jameson, J.L., Chin, W.W. J. Biol. Chem. (1998) [Pubmed]
  16. The orphan nuclear receptor, steroidogenic factor 1, regulates neuronal nitric oxide synthase gene expression in pituitary gonadotropes. Wei, X., Sasaki, M., Huang, H., Dawson, V.L., Dawson, T.M. Mol. Endocrinol. (2002) [Pubmed]
  17. Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side-chain-cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids. Sadovsky, Y., Crawford, P.A., Woodson, K.G., Polish, J.A., Clements, M.A., Tourtellotte, L.M., Simburger, K., Milbrandt, J. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  18. Adrenocorticotropic hormone-mediated signaling cascades coordinate a cyclic pattern of steroidogenic factor 1-dependent transcriptional activation. Winnay, J.N., Hammer, G.D. Mol. Endocrinol. (2006) [Pubmed]
  19. Steroidogenic factor 1 (SF-1) and SP1 are required for regulation of bovine CYP11A gene expression in bovine luteal cells and adrenal Y1 cells. Liu, Z., Simpson, E.R. Mol. Endocrinol. (1997) [Pubmed]
  20. The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis. Ingraham, H.A., Lala, D.S., Ikeda, Y., Luo, X., Shen, W.H., Nachtigal, M.W., Abbud, R., Nilson, J.H., Parker, K.L. Genes Dev. (1994) [Pubmed]
  21. Steroidogenic factor-1 controls the aldose reductase akr1b7 gene promoter in transgenic mice through an atypical binding site. Martinez, A., Val, P., Sahut-Barnola, I., Aigueperse, C., Veyssière, G., Lefrançois-Martinez, A.M. Endocrinology (2003) [Pubmed]
  22. The transcription factors steroidogenic factor-1 and SOX9 regulate expression of Vanin-1 during mouse testis development. Wilson, M.J., Jeyasuria, P., Parker, K.L., Koopman, P. J. Biol. Chem. (2005) [Pubmed]
  23. Nuclear factor Y and steroidogenic factor 1 physically and functionally interact to contribute to cell-specific expression of the mouse Follicle-stimulating hormone-beta gene. Jacobs, S.B., Coss, D., McGillivray, S.M., Mellon, P.L. Mol. Endocrinol. (2003) [Pubmed]
  24. Murine relaxin-like factor promoter: functional characterization and regulation by transcription factors steroidogenic factor 1 and DAX-1. Koskimies, P., Levallet, J., Sipilä, P., Huhtaniemi, I., Poutanen, M. Endocrinology (2002) [Pubmed]
  25. Activation of luteinizing hormone beta gene by gonadotropin-releasing hormone requires the synergy of early growth response-1 and steroidogenic factor-1. Dorn, C., Ou, Q., Svaren, J., Crawford, P.A., Sadovsky, Y. J. Biol. Chem. (1999) [Pubmed]
  26. Pituitary homeobox 2 regulates adrenal4 binding protein/steroidogenic factor-1 gene transcription in the pituitary gonadotrope through interaction with the intronic enhancer. Shima, Y., Zubair, M., Komatsu, T., Oka, S., Yokoyama, C., Tachibana, T., Hjalt, T.A., Drouin, J., Morohashi, K. Mol. Endocrinol. (2008) [Pubmed]
  27. Differential expression of steroidogenic factor-1/adrenal 4 binding protein and liver receptor homolog-1 (LRH-1)/fetoprotein transcription factor in the rat testis: LRH-1 as a potential regulator of testicular aromatase expression. Pezzi, V., Sirianni, R., Chimento, A., Maggiolini, M., Bourguiba, S., Delalande, C., Carreau, S., Andò, S., Simpson, E.R., Clyne, C.D. Endocrinology (2004) [Pubmed]
  28. Steroid receptor coactivator-1-deficient mice exhibit altered hypothalamic-pituitary-adrenal axis function. Winnay, J.N., Xu, J., O'Malley, B.W., Hammer, G.D. Endocrinology (2006) [Pubmed]
  29. Transcriptional regulation of the rat steroidogenic acute regulatory protein gene by steroidogenic factor 1. Sandhoff, T.W., Hales, D.B., Hales, K.H., McLean, M.P. Endocrinology (1998) [Pubmed]
  30. Cholesterol side-chain cleavage cytochrome P450 gene expression in the primitive gut of the mouse embryo does not require steroidogenic factor 1. Keeney, D.S., Ikeda, Y., Waterman, M.R., Parker, K.L. Mol. Endocrinol. (1995) [Pubmed]
  31. The mouse adrenocorticotropin receptor gene: cloning and characterization of its promoter and evidence for a role for the orphan nuclear receptor steroidogenic factor 1. Cammas, F.M., Pullinger, G.D., Barker, S., Clark, A.J. Mol. Endocrinol. (1997) [Pubmed]
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