Lan Zi-Jian, Gu Peili, Xu Xueping, Jackson Kathy J, DeMayo Francesco J, O'Malley Bert W, Cooney Austin J
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
EMBO J. 2003 Aug 15;22(16):4070-81. doi: 10.1093/emboj/cdg405.
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.
为了确定生殖细胞核因子（GCNF）在雌性生殖中的功能，我们构建了卵母细胞特异性GCNF基因敲除小鼠模型（GCNF(fl/fl)Zp3Cre(+)）。这些小鼠由于动情周期的间情期延长和类固醇生成异常而表现出生育力低下。这些生殖缺陷继发于卵母细胞的原发性缺陷，在间情期，GCNF(fl/fl)Zp3Cre(+)雌性小鼠的旁分泌转化生长因子-β信号分子骨形态发生蛋白15（BMP-15）和生长分化因子9（GDF-9）的表达上调。这是GCNF的直接作用，因为分子研究表明GCNF与BMP-15和GDF-9基因启动子内的DR0元件结合并抑制其报告基因活性。与这些发现一致，在GCNF(fl/fl)Zp3Cre(+)雌性小鼠中观察到异常的双卵母细胞卵泡，这表明BMP-15/GDF-9表达异常。卵母细胞中GCNF的Cre/loxP基因敲除揭示了卵巢功能的一条新调控途径。我们的结果表明，GCNF通过调节BMP-15和GDF-9的表达直接调控卵母细胞与体细胞之间的旁分泌通讯，从而影响雌性生育力。
