A unique preovulatory expression pattern plays a key role in the physiological functions of BMP-15 in the mouse
A unique preovulatory expression pattern plays a key role in the physiological functions of BMP-15 in the mouse
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DOI：
10.1073/pnas.0600507103
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发表时间：
2006-07-11
影响因子：
11.1
通讯作者：
Shimasaki, Shunichi
中科院分区：
文献类型：
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作者：
Yoshino, Osamu;McMahon, Heather E.;Shimasaki, Shunichi
骨形态发生蛋白15（BMP-15）基因的突变导致单排卵人类和绵羊的雌性不育;然而，在多排卵小鼠中，BMP-15的功能丧失仅导致排卵率降低。为了阐明这些物种特异性差异的原因，我们研究了BMP-15在小鼠卵巢中的功能作用。在这里，我们发现BMP-15的功能成熟形式在小鼠卵母细胞中几乎检测不到，直到排卵前，当它显着增加。此外，我们发现BMP-15诱导小鼠卵丘-卵母细胞复合体中的卵丘扩张。未成熟小鼠的卵母细胞培养液用孕马血清促性腺激素，然后用人绒毛膜促性腺激素也刺激卵丘扩张，这种活性被BMP-15抗体减弱。有趣的是，来自仅用孕马血清促性腺激素处理的小鼠的卵母细胞培养基没有影响。此外，BMP-15刺激卵丘细胞中EGF样生长因子以及EGF样生长因子信号传导下游的一系列分子的表达，包括环氧合酶2、透明质酸合酶2、肿瘤坏死因子刺激基因6和正五聚蛋白3，所有这些都是正常卵丘扩张所必需的。EGF受体的拮抗剂完全消除了BMP-15诱导卵丘扩张的作用。这些结果与BMP-15缺失小鼠的表型一致，其表现出正常的卵泡发生，但在排卵过程中有缺陷。因此，由BMP-15突变引起的表型的物种特异性差异可能归因于BMP-15成熟形式产生的时间变化。
Mutations in the bone morphogenetic protein 15 (BMP-15) gene cause female infertility in the monoovulatory human and sheep; however, in the polyovulatory mouse, loss-of-function of BMP-15 results only in reduced ovulation rate. To elucidate the cause of these species-specific differences, we investigated the functional role of BMP-15 in the mouse ovary. Here, we found that the functional mature form of BMP-15 is barely detectable in the mouse oocytes until just before ovulation, when it is markedly increased. Further, we found that BMP-15 induces cumulus expansion in mouse cumulus-oocyte complexes. The oocyte culture medium from immature mice primed with pregnant mare serum gonadotropin followed by human chorionic gonadotropin also stimulated cumulus expansion, and this activity was attenuated by BMP-15 antibody. Interestingly, the oocyte culture medium from mice treated with pregnant mare serum gonadotropin alone had no effect. Moreover, BMP-15 stimulated the expression of EGF-like growth factors in cumulus cells as well as a series of molecules downstream of EGF-like growth factor signaling, including cyclooxygenase 2, hyaluronan synthase 2, tumor necrosis factor-stimulated gene 6, and pentraxin 3, all of which are necessary for normal cumulus expansion. An antagonist of the EGF receptor completely abolished the effect of BMP-15 in inducing cumulus expansion. These results are consistent with the phenotype of BMP-15-null mice, which exhibit normal folliculogenesis but have defects in the ovulation process. The species-specific differences in the phenotypes caused by BMP-15 mutations may thus be attributed to the temporal variations in the production of the mature form of BMP-15.