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Target not currently curated in GtoImmuPdb
Target id: 634
Nomenclature: Germ cell nuclear factor
Systematic Nomenclature: NR6A1
Gene and Protein Information  |
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| Species | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 480 | 9q33.3 | NR6A1 | nuclear receptor subfamily 6 group A member 1 | 1,14,19-20,22 |
| Mouse | 495 | 2 B | Nr6a1 | nuclear receptor subfamily 6, group A, member 1 | 23-24,29 |
| Rat | 438 | 3q12 | Nr6a1 | nuclear receptor subfamily 6, group A, member 1 | 29 |
| Previous and Unofficial Names |
| GCNF1 | GCNF | RTR | NCNF | retinoid receptor-related testis-specific receptor | nuclear receptor subfamily 6 |
| Database Links |
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| Alphafold | Q15406 (Hs), Q64249 (Mm), E9PSV7 (Rn) |
| CATH/Gene3D | 3.30.50.10 |
| ChEMBL Target | CHEMBL1961793 (Hs) |
| Ensembl Gene | ENSG00000148200 (Hs), ENSMUSG00000063972 (Mm), ENSRNOG00000013232 (Rn) |
| Entrez Gene | 2649 (Hs), 14536 (Mm), 362125 (Rn) |
| Human Protein Atlas | ENSG00000148200 (Hs) |
| KEGG Gene | hsa:2649 (Hs), mmu:14536 (Mm), rno:362125 (Rn) |
| OMIM | 602778 (Hs) |
| Pharos | Q15406 (Hs) |
| RefSeq Nucleotide | NM_001489 (Hs), NM_010264 (Mm), NM_001159548 (Mm), NM_001159549 (Mm) |
| RefSeq Protein | NP_201591 (Hs), NP_034394 (Mm) |
| UniProtKB | Q15406 (Hs), Q64249 (Mm), E9PSV7 (Rn) |
| Wikipedia | NR6A1 (Hs) |
| Natural/Endogenous Ligands |
| Comments: Orphan |
| DNA Binding |
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| DNA Binding Comments | |||||||
| GCNF has been shown to bind to DNA on extended half site sequences identical to the SF-1 response element (SFRE : TCA AGGTCA) [3,8,13,24]). Binding to DRO element (AGGTCA AGGTCA ; which also encompasses the SFRE) was also observed, apparently with a better affinity [8,13,24,27]. PCR-coupled EMSA selection of specific binding sites indicated that the preferential target sequence is : TCA AG(G/T)TCA [27]. Although recombinant GCNF has been shown to bind DNA as a homodimer, endogenous GCNF binds DNA as hexamer first identified as the TRIF complex in P19 and ES cells [2,5-7,10]. No interaction with RXR has been detected [2,5]. | |||||||
| Co-binding Partners |
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| Name | Interaction | Effect | Reference |
| Steroidogenic factor 1 | Functional | DNA binding | 3,5-6 |
| Estrogen-related receptor-α | Functional | DNA binding | 12 |
| Estrogen-related receptor-β | Functional | DNA binding | 12 |
| Estrogen-related receptor-γ | Functional | DNA binding | 12 |
| COUP-TF1 | Functional | DNA binding | 6 |
| COUP-TF2 | Functional | DNA binding | 6 |
| Liver receptor homolog-1 | Functional | DNA binding | 9 |
| CREM tau | Functional | DNA binding | 12 |
| Main Co-regulators |
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| Name | Activity | Specific | Ligand dependent | AF-2 dependent | Comments | References |
| NCOR1 | Co-repressor | No | No | No | 6,25 | |
| NCOR2 | Co-repressor | - | No | No | 6,25 | |
| UIMC1 | Other | Yes | No | - | RAP80 interaction inhibits GCNF/NCoR interaction | 26 |
| Main Target Genes |
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| Name | Species | Effect | Technique | Comments | References |
| Gdf9 | Mouse | Repressed | Transient transfection,EMSA ,Other | Repression of GDF9 was validated in CreLox KO of GCNF in the oocyte. GCNF also represses expression of Nanog upon ES cell differentiation through binding to DR0 elements in the promoter and 3' untranslated region. | 18 |
| POU5F1 | Human | Repressed | ChIP, Transient transfection, EMSA, Other | GCNF represses Oct4 expression upon RA induced differentiation (also shown in mice and rat) | 5-7 |
| Prm1 | Mouse | Repressed | Transient transfection, EMSA | 13 | |
| Prm2 | Mouse | Repressed | Transient transfection, EMSA | 5 | |
| Bmp15 | Mouse | Repressed | Transient transfection, EMSA, Other | Repression of BMP15 was validated in CreLox KO of GCNF in the oocyte | 18 |
| Tissue Distribution
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| Tissue Distribution Comments | ||||||||
| This gene is also expressed in mice and rat. In the mouse two mRNA (7.5 and 2.4 kb) were observed due to the differential use of alternative polyadenylation sites [3,11,15,28]. In human the size of the smaller transcript is 2.2 kb [1,14,19-20,22]. Expression of GCNF in embryos and in developping brain was observed in the mouse. GCNF expression is induced in embryonic stem cells and embryocarcinoma cell lines by retinoic acid and subsequently repressed but its expression is repressed upon differentiation. Northern blot analysis has also demonstrated expression of GCNF during mouse gastrulation and early organogenesis. In situ hybridization revealed that the early expression is localized in ectodermal cells as well as in the primitive streak . At later developmental stages, the expression appears to be more restricted to the cells of the developing nervous system. In adult, the first expression studies carried out in the mouse has revealed a very narrow expression pattern in testis with very low levels in ovary, liver and kidney. In situ hybridization studies have shown a specific expression in both male and female germ cells, both in mouse and human. Northern blot analysis allowed precise determination of the expression stage of GCNF during male germ cell differentiation to the round spermatid stage. More recently, it has been shown both at the RNA and protein levels that in adult mouse testis GCNF is expressed in late pachytene spermatocytes and round spermatids. This suggests a role of GCNF in regulating both meoitic and post-meiotic events. | ||||||||
| Physiological Consequences of Altering Gene Expression
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Biologically Significant Variants
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1. Agoulnik IY, Cho Y, Niederberger C, Kieback DG, Cooney AJ. (1998) Cloning, expression analysis and chromosomal localization of the human nuclear receptor gene GCNF. FEBS Lett, 424 (1-2): 73-8. [PMID:9537518]
2. Borgmeyer U. (1997) Dimeric binding of the mouse germ cell nuclear factor. Eur J Biochem, 244 (1): 120-7. [PMID:9063454]
3. Chen F, Cooney AJ, Wang Y, Law SW, O'Malley BW. (1994) Cloning of a novel orphan receptor (GCNF) expressed during germ cell development. Mol Endocrinol, 8 (10): 1434-44. [PMID:7854358]
4. Chung AC, Katz D, Pereira FA, Jackson KJ, DeMayo FJ, Cooney AJ, O'Malley BW. (2001) Loss of orphan receptor germ cell nuclear factor function results in ectopic development of the tail bud and a novel posterior truncation. Mol Cell Biol, 21 (2): 663-77. [PMID:11134352]
5. Cooney AJ, Hummelke GC, Herman T, Chen F, Jackson KJ. (1998) Germ cell nuclear factor is a response element-specific repressor of transcription. Biochem Biophys Res Commun, 245 (1): 94-100. [PMID:9535790]
6. Fuhrmann G, Chung AC, Jackson KJ, Hummelke G, Baniahmad A, Sutter J, Sylvester I, Schöler HR, Cooney AJ. (2001) Mouse germline restriction of Oct4 expression by germ cell nuclear factor. Dev Cell, 1 (3): 377-87. [PMID:11702949]
7. Fuhrmann G, Sylvester I, Schöler HR. (1999) Repression of Oct-4 during embryonic cell differentiation correlates with the appearance of TRIF, a transiently induced DNA-binding factor. Cell Mol Biol (Noisy-le-grand), 45 (5): 717-24. [PMID:10512201]
8. Greschik H, Wurtz JM, Hublitz P, Köhler F, Moras D, Schüle R. (1999) Characterization of the DNA-binding and dimerization properties of the nuclear orphan receptor germ cell nuclear factor. Mol Cell Biol, 19 (1): 690-703. [PMID:9858592]
9. Gu P, Goodwin B, Chung AC, Xu X, Wheeler DA, Price RR, Galardi C, Peng L, Latour AM, Koller BH, Gossen J, Kliewer SA, Cooney AJ. (2005) Orphan nuclear receptor LRH-1 is required to maintain Oct4 expression at the epiblast stage of embryonic development. Mol Cell Biol, 25 (9): 3492-505. [PMID:15831456]
10. Gu P, Morgan DH, Sattar M, Xu X, Wagner R, Raviscioni M, Lichtarge O, Cooney AJ. (2005) Evolutionary trace-based peptides identify a novel asymmetric interaction that mediates oligomerization in nuclear receptors. J Biol Chem, 280 (36): 31818-29. [PMID:15994320]
11. Hirose T, O'Brien DA, Jetten AM. (1995) RTR: a new member of the nuclear receptor superfamily that is highly expressed in murine testis. Gene, 152 (2): 247-51. [PMID:7835709]
12. Hummelke GC, Cooney AJ. (2004) Reciprocal regulation of the mouse protamine genes by the orphan nuclear receptor germ cell nuclear factor and CREMtau. Mol Reprod Dev, 68 (4): 394-407. [PMID:15236322]
13. Hummelke GC, Meistrich ML, Cooney AJ. (1998) Mouse protamine genes are candidate targets for the novel orphan nuclear receptor, germ cell nuclear factor. Mol Reprod Dev, 50 (4): 396-405. [PMID:9669523]
14. Kapelle M, Krätzschmar J, Husemann M, Schleuning WD. (1997) cDNA cloning of two closely related forms of human germ cell nuclear factor (GCNF). Biochim Biophys Acta, 1352 (1): 13-7. [PMID:9177477]
15. Katz D, Niederberger C, Slaughter GR, Cooney AJ. (1997) Characterization of germ cell-specific expression of the orphan nuclear receptor, germ cell nuclear factor. Endocrinology, 138 (10): 4364-72. [PMID:9322952]
16. Lan ZJ, Chung AC, Xu X, DeMayo FJ, Cooney AJ. (2002) The embryonic function of germ cell nuclear factor is dependent on the DNA binding domain. J Biol Chem, 277 (52): 50660-7. [PMID:12381721]
17. Lan ZJ, Gu P, Xu X, Cooney AJ. (2003) Expression of the orphan nuclear receptor, germ cell nuclear factor, in mouse gonads and preimplantation embryos. Biol Reprod, 68 (1): 282-9. [PMID:12493724]
18. Lan ZJ, Gu P, Xu X, Jackson KJ, DeMayo FJ, O'Malley BW, Cooney AJ. (2003) GCNF-dependent repression of BMP-15 and GDF-9 mediates gamete regulation of female fertility. EMBO J, 22 (16): 4070-81. [PMID:12912906]
19. Lei W, Hirose T, Zhang LX, Adachi H, Spinella MJ, Dmitrovsky E, Jetten AM. (1997) Cloning of the human orphan receptor germ cell nuclear factor/retinoid receptor-related testis-associated receptor and its differential regulation during embryonal carcinoma cell differentiation. J Mol Endocrinol, 18 (2): 167-76. [PMID:9134503]
20. Schneider-Hirsch S, Bauer UM, Heiermann R, Rentrop M, Maelicke A. (1998) Cloning of the human NCNF gene. J Recept Signal Transduct Res, 18 (1): 1-13. [PMID:9493564]
21. Süsens U, Aguiluz JB, Evans RM, Borgmeyer U. (1997) The germ cell nuclear factor mGCNF is expressed in the developing nervous system. Dev Neurosci, 19 (5): 410-20. [PMID:9323461]
22. Süsens U, Borgmeyer U. (1996) Characterization of the human germ cell nuclear factor gene. Biochim Biophys Acta, 1309 (3): 179-82. [PMID:8982251]
23. Süsens U, Borgmeyer U. (2000) Genomic structure of the gene for mouse germ cell nuclear factor (GCNF). Genome Biol, 1 (3): RESEARCH0006. [PMID:11178239]
24. Süsens U, Borgmeyer U. (2001) Genomic structure of the gene for mouse germ-cell nuclear factor (GCNF). II. Comparison with the genomic structure of the human GCNF gene. Genome Biol, 2 (5): RESEARCH0017. [PMID:11387038]
25. Yan Z, Jetten AM. (2000) Characterization of the repressor function of the nuclear orphan receptor retinoid receptor-related testis-associated receptor/germ cell nuclear factor. J Biol Chem, 275 (45): 35077-85. [PMID:10940306]
26. Yan Z, Kim YS, Jetten AM. (2002) RAP80, a novel nuclear protein that interacts with the retinoid-related testis-associated receptor. J Biol Chem, 277 (35): 32379-88. [PMID:12080054]
27. Yan ZH, Medvedev A, Hirose T, Gotoh H, Jetten AM. (1997) Characterization of the response element and DNA binding properties of the nuclear orphan receptor germ cell nuclear factor/retinoid receptor-related testis-associated receptor. J Biol Chem, 272 (16): 10565-72. [PMID:9099702]
28. Yang G, Zhang YL, Buchold GM, Jetten AM, O'Brien DA. (2003) Analysis of germ cell nuclear factor transcripts and protein expression during spermatogenesis. Biol Reprod, 68 (5): 1620-30. [PMID:12606326]
29. Zhang Z, Burch PE, Cooney AJ, Lanz RB, Pereira FA, Wu J, Gibbs RA, Weinstock G, Wheeler DA. (2004) Genomic analysis of the nuclear receptor family: new insights into structure, regulation, and evolution from the rat genome. Genome Res, 14 (4): 580-90. [PMID:15059999]
6A. Germ cell nuclear factor receptors: Germ cell nuclear factor. Last modified on 22/03/2016. Accessed on 19/03/2025. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=634.
