Germ cell nuclear factor (GCNF) was originally found in the mouse as a germ cell-specific orphan member of the nuclear receptor superfamily. It is expressed in the oocyte and testis spermatogenic cells (Chen et al., 1994).
Extra-Germ Cell Expression of Mouse Nuclear Receptor Subfamily 6, Group A, Member 1 (NR6A1). Lan ZJ et al. Nuclear receptor subfamily 6, group A, member 1 (NR6A1) is an orphan member of the nuclear receptor superfamily and required for normal mouse embryonic development. In adult mice, NR6A1 is predominantly expressed in spermatogenic cells and growing oocytes of the gonads and plays a role in female reproduction by modulating the transcription of oocyte-specific genes, bone morphogenetic protein 15 (Bmp15) and growth differentiation factor 9 (Gdf9). In our goal to further understand the functional role of NR6A1 during postnatal development, we generated a Nr6a1:beta-galactosidase (LacZ) knock-in reporter (Nr6a1(LacZ/+)) mouse line in which Nr6a1:LacZ fusion gene was expressed, and then characterized Nr6a1 expression in these reporter mice by performing LacZ staining. RT-PCR analyses showed that Nr6a1 were expressed in a variety of somatic tissues (e.g. oviduct and lung) other than gonads of normal adult mice. In adult Nr6a1(LacZ/+) mice, robust LacZ staining was observed in the gametes of gonads. Strong positive LacZ staining was also observed in the sperm of epididymis, epithelial cells of oviduct and the bronchioles within the lung. In addition, positive LacZ staining was observed in other somatic tissues including cerebral cortex, cerebellum and thalamus of brain, pars intermedia and pars anterior of pituitary, parathyroid and islet of pancreas in adult Nr6a1(LacZ/+) mice. NR6A1 expression in sperm within the epididymis, epithelial cells within the oviduct and the bronchioles of lung were further confirmed by immunohistochemical studies. It can be concluded that Nr6a1 is not only expressed in the germ cells of mouse gonads, but also expressed in a variety of somatic tissues including reproductive tissues such as the epididymis, oviduct, brain and pituitary. The extra-germ cell expression of NR6A1 makes it a less attractive contraceptive.
NCBI Summary:
This gene encodes an orphan nuclear receptor which is a member of the nuclear hormone receptor family. Its expression pattern suggests that it may be involved in neurogenesis and germ cell development. The protein can homodimerize and bind DNA, but in vivo targets have not been identified. The gene expresses three alternatively spliced transcript variants.
General function
Nucleic acid binding, DNA binding, Transcription factor
Comment
Although no ligand for GCNF has been identified, GCNF binds to the sequence TCAAGGTCA that includes the steroidogenic factor-1 half-site
Cellular localization
Nuclear
Comment
Ovarian function
Oogenesis
Comment
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Expression regulated by
Comment
Ovarian localization
Oocyte
Comment
Follicle stages
Primary, Secondary, Antral, Preovulatory
Comment
The expression of GCNF was found in growing oocytes that have not completed the first meiotic division (Katz et al., 1997).
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment:Lan ZJ, et al reported the GCNF-dependent repression of BMP-15 and GDF-9 mediates gamete regulation of female fertility.
To determine the function of germ cell nuclear factor (GCNF) in female reproduction, we generated an oocyte-specific GCNF knockout mouse model (GCNF(fl/fl)Zp3Cre(+)). These mice displayed hypofertility due to prolonged diestrus phase of the estrous cycle and aberrant steroidogenesis. These reproductive defects were secondary to a primary defect in the oocytes, in which expression of the paracrine transforming growth factor-beta signaling molecules, bone morphogenetic protein 15 (BMP-15) and growth differentiation factor 9 (GDF-9), were up-regulated in GCNF(fl/fl)Zp3Cre(+) females at diestrus. This was a direct effect of GCNF, as molecular studies showed that GCNF bound to DR0 elements within the BMP-15 and GDF-9 gene promoters and repressed their reporter activities. Consistent with these findings, abnormal double-oocyte follicles, indicative of aberrant BMP-15/GDF-9 expression, were observed in GCNF(fl/fl)Zp3Cre(+) females. The Cre/loxP knockout of GCNF in the oocyte has uncovered a new regulatory pathway in ovarian function. Our results show that GCNF directly regulates paracrine communication between the oocyte and somatic cells by regulating the expression of BMP-15 and GDF-9, to affect female fertility.