Oocyte-specific overexpression of mouse bone morphogenetic protein-15 leads to accelerated folliculogenesis and an early onset of acyclicity in transgenic mice
Oocyte-specific overexpression of mouse bone morphogenetic protein-15 leads to accelerated folliculogenesis and an early onset of acyclicity in transgenic mice
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DOI：
10.1210/en.2007-1550
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发表时间：
2008-06-01
期刊：
影响因子：
4.8
通讯作者：
Shimasaki, Shunichi
中科院分区：
文献类型：
--
作者：
McMahon, Heather E.;Hashimoto, Osamu;Shimasaki, Shunichi
尽管bmp 15基因突变导致母羊和妇女由于卵泡发育缺陷而不育，但缺乏骨形态发生蛋白（BMP）-15的雌性小鼠的大多数缺陷仅限于排卵过程，这支持了以下观察结果：直到LH峰后，在体内卵母细胞中几乎检测不到功能性小鼠BMP-15。此外，小鼠BMP-15前蛋白在转染细胞中不被加工成功能性成熟蛋白。然而，加工由人前区、人切割位点和小鼠成熟区组成的嵌合蛋白（称为hhmBMP-15），并分泌成熟蛋白。为了研究BMP-15在卵泡发生中的作用，我们产生了过度表达hhmBMP-15的转基因小鼠，仅在卵泡发生期间的卵母细胞中，并证实了小鼠BMP-15成熟蛋白的过度表达。未成熟的转基因小鼠表现出加速卵泡生长，初级卵泡减少，次级卵泡增加。未成熟小鼠颗粒细胞有丝分裂指数增加，FSH受体mRNA表达降低。成年小鼠的窝仔数正常，但闭锁的窦状卵泡数量增加。有趣的是，衰老小鼠表现出早期发作的非周期性，其特征在于增加的间情期长度和早期发生的恒定间情期。这些发现表明BMP-15在体内促进卵泡生长和阻止卵泡成熟的作用，导致转基因小鼠卵巢储备早期下降。因此，在野生型小鼠早期卵泡形成过程中缺乏小鼠BMP-15可能与其多排卵性质以及随着小鼠年龄的增长卵巢功能的保留有关。
Whereas mutations in the bmp15 gene cause infertility in ewes and women due to defects in folliculogenesis, most defects in female mice lacking bone morphogenetic protein (BMP)-15 are confined to the ovulation process, supportive of the observation that functional mouse BMP-15 is barely detected in oocytes in vivo until after the LH surge. In addition, the mouse BMP-15 proprotein is not processed into the functional mature protein in transfected cells. However, a chimeric protein consisting of the human proregion, human cleavage site, and mouse mature region ( termed hhmBMP-15) is processed and the mature protein secreted. To study the role of BMP-15 in folliculogenesis, we generated transgenic mice overexpressing hhmBMP-15, exclusively in oocytes during folliculogenesis and confirmed the overexpression of mouse BMP-15 mature protein. Immature transgenic mice exhibited accelerated follicle growth with decreased primary follicles and an increase in secondary follicles. Granulosa cells of immature mice displayed an increased mitotic index and decreased FSH receptor mRNA expression. Adult mice had normal litter sizes but an increased number of atretic antral follicles. Interestingly, aging mice exhibited an early onset of acyclicity marked by increased diestrus length and early occurrence of constant diestrus. These findings indicate the role of BMP-15 in vivo in promoting follicle growth and preventing follicle maturation, resulting in an early decline in the ovarian reserve of transgenic mice. Therefore, the lack of mouse BMP-15 during early folliculogenesis in the wild-type mice may be relevant to their polyovulatory nature as well as the preservation of ovarian function as the mice age.