Disease relevance of NR6A1

• 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 [1].
• In this study, we examine the expression of RTR in murine placenta and several human placental choriocarcinoma cell lines [2].
• We show that expression of CRIPTO-1 is directly repressed by GCNF during differentiation of the human teratocarcinoma cell line, NT2 [3].
• Renal patients (end-stage renal failure (ESRF) and transplant recipients (RTR)) exhibit both hyperhomocysteinemia and endothelial dysfunction with increasing evidence of a causative link between the 2 conditions [4].
• CONCLUSION: Both recipient and donor factors contribute to hypertension in RTR [5].

High impact information on NR6A1

• Here we show that the orphan nuclear receptor GCNF initiates Oct4 repression and DNA methylation by the differential recruitment of MBD (methylated CpG binding domain) factors to the promoter [6].
• GCNF initiates the repression and epigenetic modification of Oct4 gene during ES cell differentiation [6].
• During development, GCNF exhibits a restricted brain-specific expression pattern, whereas GCNF expression in the adult is germ cell specific [7].
• No natural GCNF target gene has yet been identified, but recent data demonstrate specific and high-affinity binding of GCNF either to the direct repeat DNA element AGGTCAAGGTCA (DR0) or to extended half-sites, such as TCAAGGTCA [7].
• Characterization of the DNA-binding and dimerization properties of the nuclear orphan receptor germ cell nuclear factor [7].

Chemical compound and disease context of NR6A1

• Induction of differentiation of mouse embryonal carcinoma F9 cells and human embryonal carcinoma NTERA-2 clone D1 (NT2/D1) cells by all-trans retinoic acid was accompanied by a down-regulation of GCNF/RTR [1].

Biological context of NR6A1

• Mammalian two-hybrid analysis demonstrated that RAP80 was able to interact with the retinoid-related testis-associated receptor (RTR), an orphan receptor that has been implicated in the control of embryonic development and spermatogenesis [8].
• Deletion and point mutation analyses revealed that part of the hinge domain of RTR is required for this interaction [8].
• We demonstrate that RTR can suppress the transcriptional activation induced by the estrogen receptor related-receptor alpha1 through its response element [9].
• In addition, RTR inhibits basal transcriptional activation, indicating that it functions as an active repressor [9].
• Our data suggest a down-regulation of CREMtau-mediated gene expression by GCNF, which might be a general regulation mechanism for several postmeiotically expressed genes with a temporal expression peak during early spermatid development [10].

Anatomical context of NR6A1

• We report the cloning of a cDNA encoding a new variant of human GCNF from human testis and its expression analysis [11].
• GCNF/RTR was also highly expressed in embryonic stem cells and embryonal carcinoma cells but repressed in its differentiated derivatives [1].
• These results suggest the possibility of cross-talk between RTR and ERR alpha receptor signalling pathways in trophoblasts [2].
• Northern blot analysis using RNA from different testicular cell types showed that RTR mRNA is not expressed in early germ cells or Sertoli cells but is most abundant in round spermatids [12].
• In addition, full neuronal differentiation is not observed in the midbrain region of GCNF(-/-) embryos [13].

Associations of NR6A1 with chemical compounds

• Germ cell nuclear factor relieves cAMP-response element modulator tau-mediated activation of the testis-specific promoter of human mitochondrial glycerol-3-phosphate dehydrogenase [10].
• Due to the lack of a conserved transcriptional activation function 2 core motif (AF-2 AD core) in the helix 12 region of the GCNF LBD, it has been suggested that GCNF functions as a repressor of transcription [14].
• In trophoblasts, RTR was co-expressed with the estrogen-related receptors ERR alpha and ERR beta [2].
• (ii) SF-1, which controls the fate of two steroid hormone-producing organs, adrenals and gonads, is descended from the invertebrate Ftz-F1 gene, and its only known paralogue is GCNF-1 [15].
• This review will discuss 18 supplementation studies conducted in ESRF and 6 in RTR investigating the effects of nutritional therapy to lower homocysteine [4].

Physical interactions of NR6A1

• To identify the regions in RTR essential for the binding of RTR to N-CoR, the effect of various deletion and point mutations on this interaction was examined [9].
• GCNF binds as a homodimer to a direct repeat element with zero nucleotides between the reiterated sequence AGGTCA [16].

Other interactions of NR6A1

• Our results demonstrate that RTR can function as an active transcriptional repressor and that this repression can be mediated through interactions with the co-repressor N-CoR [9].
• GCNF has been shown to be a repressor of the protamine and Oct4 genes [16].
• Nuclear orphan receptors oestrogen receptor-related receptor alpha (ERRalpha) and germ cell nuclear factor (GCNF) are expressed to significant levels in MDA-MB 231 cells [17].

Analytical, diagnostic and therapeutic context of NR6A1

• Northern blot analysis using poly(A)+ RNA from different human tissues showed that GCNF/RTR mRNA is most abundantly expressed in the testis [1].
• Southern blot analysis of the human genomic DNA indicates that the GCNF gene is not closely related to other members within the nuclear receptor superfamily [11].
• 1. In situ hybridization analysis of GCNF expression in the testis shows that human GCNF is expressed exclusively in germ cells [11].
• Examination of RTR expression in murine placental tissue by immunohistochemistry demonstrated the presence of RTR protein in the nuclei of giant trophoblasts and spongiotrophoblasts [2].
• Temporary up-regulation in NT2/D1 cells after treatment with atRA suggests that hGCNF is important for human neural determination and differentiation [18].

References