Synergistic roles of BMP15 and GDF9 in the development and function of the oocyte-cumulus cell complex in mice: genetic evidence for an oocyte-granulosa cell regulatory loop
Synergistic roles of BMP15 and GDF9 in the development and function of the oocyte-cumulus cell complex in mice: genetic evidence for an oocyte-granulosa cell regulatory loop
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DOI：
10.1016/j.ydbio.2004.08.020
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发表时间：
2004-12-01
影响因子：
2.7
通讯作者：
Eppig, JJ
中科院分区：
文献类型：
--
作者：
Su, YQ;Wu, XM;Eppig, JJ
骨形态发生蛋白15 （Bone morphogenetic protein 15, BMP15）和生长分化因子9 （growth differentiation factor 9, GDF9）是卵母细胞特异性生长因子，在大多数哺乳动物颗粒细胞发育和生育中发挥关键作用。我们通过评估Gdj9(+/-)Bmp15(-/-)[双突变（DM）]小鼠的积云扩张、卵母细胞成熟、受精和着床前胚胎发生，评估了这些旁分泌因子在积云细胞和卵母细胞的发育和功能中的作用。我们发现，在DM卵母细胞-卵丘细胞复合物中，卵丘的扩张以及透明质子合成酶2 (Has2) mRNA的表达受损。与正常野生型（WT）卵母细胞共培养不能纠正这种异常的积云扩张，这表明DM中积云细胞的发育和/或分化，直到排卵前黄体生成素（LH）激增的阶段，都受到了损害。此外，DM卵母细胞不能使FSH诱导WT卵母细胞切除（OOX）的积云扩张。此外，LH诱导的卵母细胞减数分裂恢复在体内明显延迟，这种延迟的减数分裂恢复与积云细胞中丝裂原活化蛋白激酶（MAPK）的激活降低有关，提示GDF9和BMP15在排卵前LH激增后也调节积云细胞的功能。尽管体外自发卵母细胞成熟正常发生，但DM患者的卵母细胞受精和着床前胚胎发生明显改变，这表明GDF9和BMP15的充分补充对卵母细胞的发育和功能至关重要。由于在小鼠卵母细胞中尚未发现GDF9和BMP15的受体，因此BMP15和GDF9基因突变对卵母细胞发育和功能的影响必须通过先影响颗粒细胞后影响卵母细胞的间接方式产生。因此，本研究为卵母细胞-颗粒细胞调节环的存在和功能提供了进一步的证据。(C) 2004 Elsevier Inc .版权所有
Bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) are oocyte-specific growth factors that appear to play key roles in granulosa cell development and fertility in most mammalian species. We have evaluated the role(s) of these paracrine factors in the development and function of both the cumulus cells and oocytes by assessing cumulus expansion, oocyte maturation, fertilization, and preimplantation embryogenesis in Gdj9(+/-)Bmp15(-/-) [hereafter, double mutant (DM)] mice. We found that cumulus expansion, as well as the expression of hyaluronon synthase 2 (Has2) mRNA was impaired in DM oocyte-cumulus cell complexes. This aberrant cumulus expansion was not remedied by coculture with normal wild-type (WT) oocytes, indicating that the development and/or differentiation of cumulus cells in the DM, up to the stage of the preovulatory luteinizing hormone (LH) surge, is impaired. In addition, DM oocytes failed to enable FSH to induce cumulus expansion in WT oocytectomized (OOX) cumulus. Moreover, LH-induced oocyte meiotic resumption was significantly delayed in vivo, and this delayed resumption of meiosis was correlated with the reduced activation of mitogen-activated protein kinase (MAPK) in the cumulus cells, thus suggesting that GDF9 and BMP15 also regulate the function of cumulus cells after the preovulatory LH surge. Although spontaneous in vitro oocyte maturation occurred normally, oocyte fertilization and preimplantation embryogenesis were significantly altered in the DM, suggesting that the full complement of both GDF9 and BMP15 are essential for the development and function of oocytes. Because receptors for GDF9 and BMP15 have not yet been identified in mouse oocytes, the effects of the mutations in the Bmp15 and Gdf9 genes on oocyte development and functions must be produced indirectly by first affecting the granulosa cells and then the oocyte. Therefore, this study provides further evidence for the existence and functioning of an oocyte-granulosa cell regulatory loop. (C) 2004 Elsevier Inc, All rights reserved.