TABLE 25

GCNF

Receptor nomenclature NR6A1
Receptor code 4.1:OR:6:A1
Other names RTR, NCNF, TRIF
Molecular information Hs: 480aa, Q15406, chr. 9q3315
Rn: 453aa, chr. 3q116
Mm: 495aa, Q64249, chr. 2 B711
DNA binding
   Structure Homodimer
   HRE core sequence TCA AGGTCA (DR-0, half-site)7,1119
Partners SF-1 (functional): DNA binding7,17,1 9; CREMτ (functional): DNA binding20; ERRα, ERRβ, ERRγ (functional): DNA binding21; COUP-TFI, COUP-TFII (functional): DNA binding19; LRH-1 (functional): DNA binding22
Agonists
Antagonists
Coactivators RAP8023
Corepressors NCOR1, NCOR219,24
Biologically important isoforms GCNF2 {Hs}: uses two alternate in-frame splice sites resulting in an isoform that has the same N and C termini but is shorter than GCNF5; GCNF3 {Hs}: this variant lacks an alternate in-frame segment and uses an alternate in-frame splice site, resulting in an isoform that has the same N and C termini but is shorter than GCNF5
Tissue distribution Developmental: brain, ectodermal cells, primitive streak, nervous system; adult: testis, ovary, liver, kidney, germ cells {Hs, Mm, Rn} [Northern blot, in situ hybridization, Western blot, immunohistology]1,2,69,17,19,2529
Functional assays
Main target genes Repressed: Oct4 {Hs, Mm, Rn},17,19 PRM1 {Mm},20 PRM2 {Mm},20 BMP15 {Mm},30 GDF-9 {Mm}30
Mutant phenotype Homozygote GCNF-null mice have cardiovascular abnormalities, defective trunk development, impaired somite formation, failure to turn, open neural tube, hindgut, protrusion of the tailbud outside the yolk sac, and die by embryonic day 10.5 {Mm} [knockout]17,19,28,31; hypofertility because of prolonged diestrus phase of the estrous cycle and aberrant steroidogenesis {Mm} [tissue-specific Cre/Lox knockout in the oocyte]30
Human disease
  • aa, amino acids; chr., chromosome; HRE, hormone response element; CREM, cAMP-response element modulator

  • 1. Lei W, Hirose T, Zhang LX, Adachi H, Spinella MJ, Dmitrovsky E, and 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: 167-176

  • 2. Agoulnik IY, Cho Y, Niederberger C, Kieback DG, and Cooney AJ (1998) Cloning, expression analysis and chromosomal localization of the human nuclear receptor gene GCNF. FEBS Lett 424: 73-78

  • 3. Schneider-Hirsch S, Bauer UM, Heiermann R, Rentrop M, and Maelicke A (1998) Cloning of the human NCNF gene. J Recept Signal Transduct Res 18: 1-13

  • 4. Susens U and Borgmeyer U (1996) Characterization of the human germ cell nuclear factor gene. Biochim Biophys Acta 1309: 179-182

  • 5. Kapelle M, Kratzschmar J, Husemann M, and Schleuning WD (1997) cDNA cloning of two closely related forms of human germ cell nuclear factor (GCNF). Biochim Biophys Acta 1352: 13-17

  • 6. Zhang Z, Burch PE, Cooney AJ, Lanz RB, Pereira FA, Wu J, Gibbs RA, Weinstock G, and Wheeler DA (2004) Genomic analysis of the nuclear receptor family: new insights into structure, regulation, and evolution from the rat genome. Genome Res 14: 580-590

  • 7. Chen F, Cooney AJ, Wang Y, Law SW, and O'Malley BW (1994) Cloning of a novel orphan receptor (GCNF) expressed during germ cell development. Mol Endocrinol 8: 1434-1444

  • 8. Hirose T, O'Brien DA, and Jetten AM (1995) RTR: a new member of the nuclear receptor superfamily that is highly expressed in murine testis. Gene 152: 247-251

  • 9. Bauer UM, Schneider-Hirsch S, Reinhardt S, Pauly T, Maus A, Wang F, Heiermann R, Rentrop M, and Maelicke A (1997) Neuronal cell nuclear factor—a nuclear receptor possibly involved in the control of neurogenesis and neuronal differentiation. Eur J Biochem 249: 826-837

  • 10. Susens U and Borgmeyer U (2000) Genomic structure of the gene for mouse germ cell nuclear factor (GCNF). Genome Biol 1: RESEARCH0006

  • 11. Susens U and 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: RESEARCH0017

  • 12. Hummelke GC, Meistrich ML, and Cooney AJ (1998) Mouse protamine genes are candidate targets for the novel orphan nuclear receptor, germ cell nuclear factor. Mol Reprod Dev 50: 396-405

  • 13. Greschik H, Wurtz JM, Hublitz P, Kohler F, Moras D, and Schule R (1999) Characterization of the DNA-binding and dimerization properties of the nuclear orphan receptor germ cell nuclear factor. Mol Cell Biol 19: 690-703

  • 14. Yan ZH, Medvedev A, Hirose T, Gotoh H, and 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: 10565-10572

  • 15. Borgmeyer U (1997) Dimeric binding of the mouse germ cell nuclear factor. Eur J Biochem 244: 120-127

  • 16. Gu R, Morgan DH, Sattar M, Xu X, Wagner R, Raviscioni M, Lichtarge O, and Cooney AJ (2005) Evolutionary trace-based peptides identify a novel asymmetric interaction that mediates oligomerization in nuclear receptors. J Biol Chem 280: 31818-31829

  • 17. Cooney AJ, Hummelke GC, Herman T, Chen F, and Jackson KJ (1998) Germ cell nuclear factor is a response element-specific repressor of transcription. Biochem Biophys Res Commun 245: 94-100

  • 18. Fuhrmann G, Sylvester I, and Scholer 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: 717-724

  • 19. Fuhrmann G, Chung AC, Jackson KJ, Hummelke G, Baniahmad A, Sutter J, Sylvester I, Scholer HR, and Cooney AJ (2001) Mouse germline restriction of Oct4 expression by germ cell nuclear factor. Dev Cell 1: 377-387

  • 20. Hummelke GC and Cooney AJ (2004) Reciprocal regulation of the mouse protamine genes by the orphan nuclear receptor germ cell nuclear factor and CREMτ. Mol Reprod Dev 68: 394-407

  • 21. Mehta DV, Kim YS, Dixon D, and Jetten AM (2002) Characterization of the expression of the retinoid-related, testis-associated receptor (RTR) in trophoblasts. Placenta 23: 281-287

  • 22. Gu P, Goodwin B, Chung AC, Xu X, Wheeler DA, Price RR, Galardi C, Peng L, Latour AM, Koller BH, et al. (2005) Orphan nuclear receptor LRH-1 is required to maintain Oct4 expression at the epiblast stage of embryonic development. Mol Cell Biol 25: 3492-3505

  • 23. Yan Z, Kim YS, and Jetten AM (2002) RAP80, a novel nuclear protein that interacts with the retinoid-related testis-associated receptor. J Biol Chem 277: 32379-32388

  • 24. Yan Z and 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: 35077-35085

  • 25. Katz D, Niederberger C, Slaughter GR, and Cooney AJ (1997) Characterization of germ cell-specific expression of the orphan nuclear receptor, germ cell nuclear factor. Endocrinology 138: 4364-4372

  • 26. Yang G, Zhang YL, Buchold GM, Jetten AM, and O'Brien DA (2003) Analysis of germ cell nuclear factor transcripts and protein expression during spermatogenesis. Biol Reprod 68: 1620-1630

  • 27. Susens U, Aguiluz JB, Evans RM, and Borgmeyer U (1997) The germ cell nuclear factor mGCNF is expressed in the developing nervous system. Dev Neurosci 19: 410-420

  • 28. Chung AC, Katz D, Pereira FA, Jackson KJ, DeMayo FJ, Cooney AJ, and 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: 663-677

  • 29. Lan ZJ, Gu P, Xu X, and Cooney AJ (2003) Expression of the orphan nuclear receptor, germ cell nuclear factor, in mouse gonads and preimplantation embryos. Biol Reprod 68: 282-289

  • 30. Lan ZJ, Gu P, Xu X, Jackson KJ, DeMayo FJ, O'Malley BW, and Cooney AJ (2003) GCNF-dependent repression of BMP-15 and GDF-9 mediates gamete regulation of female fertility. EMBO (Eur Mol Biol Organ) J 22: 4070-4081

  • 31. Lan ZJ, Chung AC, Xu X, DeMayo FJ, and Cooney AJ (2002) The embryonic function of germ cell nuclear factor is dependent on the DNA binding domain. J Biol Chem 277: 50660-50667