Disease relevance of Nr6a1

• To test the prediction that GCNF is additionally required for neuronal differentiation, we used the mouse embryonal carcinoma cell line PCC7-Mz1, which represents an advantageous model to study neuronal cells from the stage of fate choice until the acquirement of functional competence [1].

High impact information on Nr6a1

• The Cre/loxP knockout of GCNF in the oocyte has uncovered a new regulatory pathway in ovarian function [2].
• Inactivation of the gene encoding the orphan nuclear receptor GCNF showed that it plays an important role in the repression of Oct4 expression in somatic cells during early embryonic development [3].
• Orphan nuclear receptor GCNF is required for the repression of pluripotency genes during retinoic acid-induced embryonic stem cell differentiation [3].
• These findings establish a central role for GCNF in the repression of pluripotency gene expression during retinoic acid-induced ES cell differentiation [3].
• GCNF-/- ES cells were isolated to study the function of GCNF in the down-regulation of pluripotency genes during differentiation [3].

Biological context of Nr6a1

• GCNF therefore defines a novel nuclear receptor-signaling pathway that may regulate a subset of genes involved in the terminal differentiation process of spermatogenesis, exemplified by the protamines [4].
• Furthermore, we have previously identified a sequence to which GCNF can bind, which consists of a direct repeat of the core halfsite AGGTCA with zero base pairs spacing the repeats (DRO) [5].
• GCNF binds as a homodimer to direct repeat response elements of the consensus half-site sequence, AGGTCA, with 0 bp spacing (DR0) [4].
• A boundary for histone acetylation allows distinct expression patterns of the Ad4BP/SF-1 and GCNF loci in adrenal cortex cells [6].
• GCNF overexpression in embryonal cells represses Oct4 gene and transgene activities, and we establish a link to transcriptional corepressors mediating repression by GCNF [7].

Anatomical context of Nr6a1

• Germ cell nuclear factor (GCNF) is a member of the nuclear receptor superfamily, which is expressed in the adult predominantly in the male and female germ cells [4].
• Furthermore, by using antibodies directed against GCNF, we detect endogenous GCNF in testis nuclear extracts and elutriated round spermatid nuclear extracts in Western blots [5].
• This evidence supports the hypothesis that GCNF mediates a novel signaling pathway, two targets of which may be the Prm1 and Prm2 genes in spermatids [5].
• Immunohistochemical analysis using an ELP-specific antibody showed that expression was very restricted within the testis to the postmeiotic germ cells, and in the ovary to interstitial/luteal cells, cell-types known to express GCNF and SF-1, respectively [8].
• Our studies suggest that GCNF is critical in repressing Oct4 gene activity as pluripotent stem cells differentiate and in confining Oct4 expression to the germline [7].

Associations of Nr6a1 with chemical compounds

• We generated stable transfectants that express gcnf sense or antisense RNA under the control of a tetracycline-regulated promoter [1].
• Androgen down-regulated and region-specific expression of germ cell nuclear factor in mouse epididymis [9].
• In addition, I show that there is no in vitro interaction of GCNF with the retinoid X receptor, a promiscous partner of many nuclear receptors [10].

Regulatory relationships of Nr6a1

• The murine nuclear orphan receptor GCNF is expressed in the XY body of primary spermatocytes [11].
• Transient transfection assays in NIH 3T3 cells further demonstrated that GCNF fused to a VP16 activation domain stimulated transcription from reporter constructs containing the c-mos GCNF binding site [12].

Other interactions of Nr6a1

• Within this YAC, Ftz-F1 is centrally located and flanked by genes encoding a second orphan nuclear receptor, germ cell nuclear factor, and proteasome (prosome, macropain) subunit beta type 7 [13].
• The mouse protamine 1 and 2 (Prm1 and Prm2) genes therefore are potential target genes for GCNF regulation [5].
• Moreover, the induction of Oct-3/4 repressors Cdx-2, Coup-tf1, and GCNF was stimulated by GABPalpha knockdown [14].
• Interestingly, the tailbud of GCNF(-/-) embryos develops ectopically outside the yolk sac [15].
• It implies that some androgen-regulated gene expressions located at the corpus principal cells might be controlled by GCNF [9].

Analytical, diagnostic and therapeutic context of Nr6a1

• Similarly, Northern analysis and specific in situ hybridization show that GCNF expression first occurs in testis of 20-day-old mice, when round spermatids first emerge [16].
• METHODS: The epididymal sections from different postnatal days were stained for GCNF by the indirect immunofluorescence technique and digital photographs were taken by a Carl Zeiss confocal microscope [17].

References