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.
Lan
Zi-Jian
ZJ
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Gu
Peili
P
Xu
Xueping
X
Jackson
Kathy J
KJ
DeMayo
Francesco J
FJ
O'Malley
Bert W
BW
Cooney
Austin J
AJ
D000818:Animals; D055430:Bone Morphogenetic Protein 15; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004527:Egg Proteins / Q000378:metabolism; D005260:Female; D005298:Fertility / Q000502:physiology*; D005786:Gene Expression Regulation; D055429:Growth Differentiation Factor 9; D019426:Integrases / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1; D009865:Oocytes / Q000166:cytology; D010053:Ovary / Q000166:cytology / Q000378:metabolism; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D019076:Transgenes; D014764:Viral Proteins / Q000378:metabolism; D015044:Zona Pellucida / Q000378:metabolism; D000072216:Zona Pellucida Glycoproteins
C525901:BMP15 protein, human; C525902:Bmp15 protein, mouse; D055430:Bone Morphogenetic Protein 15; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D004527:Egg Proteins; C525897:GDF9 protein, human; C525898:Gdf9 protein, mouse; D055429:Growth Differentiation Factor 9; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C539950:NR6A1 protein, human; C539954:Nr6a1 protein, mouse; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; D014764:Viral Proteins; D000072216:Zona Pellucida Glycoproteins; C045073:Cre recombinase; D019426:Integrases