Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function.
Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function.
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DOI：
10.1210/mend.15.6.0662
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发表时间：
2001-06
影响因子：
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通讯作者：
Changning Yan;Pei Wang;J. Demayo;F. DeMayo;J. Elvin;C. Cariño;S. Prasad;Sheri Skinner;B. Dunbar-B
中科院分区：
文献类型：
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作者：
Changning Yan;Pei Wang;J. Demayo;F. DeMayo;J. Elvin;C. Cariño;S. Prasad;Sheri Skinner;B. Dunbar-B
在过去的十年中，敲除小鼠技术已被用于定义卵巢表达基因的基本作用并揭示遗传相互作用。特别是，我们已经使用这种技术来研究转化生长因子-β超家族的多个成员的功能，这些成员包括β-内酰胺酶、激活素和生长分化因子9（GDF-9或Gdf 9）。缺乏GDF-9的基因敲除小鼠由于在初级卵泡阶段卵泡发生的阻断而不育。此外，重组GDF-9在排卵期调节多种卵丘颗粒细胞功能，包括透明质酸合成和卵丘扩张。我们还从小鼠和人类中克隆了GDF-9的卵母细胞特异性同源物，称为骨形态发生蛋白15（BMP-15或Bmp 15）。为了确定BMP-15在小鼠中的功能，我们产生了胚胎干细胞和敲除小鼠，这些小鼠在这个X连锁基因中具有无效突变。雄性嵌合和Bmp 15缺失小鼠是正常的和可生育的。与Bmp 15缺失雄性和Gdf 9敲除雌性相反，Bmp 15缺失雌性（Bmp 15（-/-））生育力低下，通常具有最小的卵巢组织病理学缺陷，但表现出排卵和受精率降低。为了进一步解释GDF-9和BMP-15之间可能的直接或间接遗传相互作用，我们已经产生了缺乏这些相关同源物的一个或两个等位基因的双突变小鼠。双纯合子雌性（Bmp 15（-/-）Gdf 9（-/-））显示卵母细胞丢失和囊肿，类似于Gdf 9（-/-）突变体。相比之下，Bmp 15（-/-）Gdf 9（+/-）雌性小鼠比Bmp 15（-/-）雌性小鼠具有更严重的生育缺陷，这似乎是由于卵巢卵泡发生、卵丘细胞生理学和受精的异常。因此，完整的Bmp 15和Gdf 9等位基因的剂量直接影响卵泡发生和排卵期卵母细胞的命运。这些研究对人类生育控制和维持生育力和正常卵巢生理具有重要意义。
Knockout mouse technology has been used over the last decade to define the essential roles of ovarian-expressed genes and uncover genetic interactions. In particular, we have used this technology to study the function of multiple members of the transforming growth factor-beta superfamily including inhibins, activins, and growth differentiation factor 9 (GDF-9 or Gdf9). Knockout mice lacking GDF-9 are infertile due to a block in folliculogenesis at the primary follicle stage. In addition, recombinant GDF-9 regulates multiple cumulus granulosa cell functions in the periovulatory period including hyaluronic acid synthesis and cumulus expansion. We have also cloned an oocyte-specific homolog of GDF-9 from mice and humans, which is termed bone morphogenetic protein 15 (BMP-15 or Bmp15). To define the function of BMP-15 in mice, we generated embryonic stem cells and knockout mice, which have a null mutation in this X-linked gene. Male chimeric and Bmp15 null mice are normal and fertile. In contrast to Bmp15 null males and Gdf9 knockout females, Bmp15 null females (Bmp15(-/-)) are subfertile and usually have minimal ovarian histopathological defects, but demonstrate decreased ovulation and fertilization rates. To further decipher possible direct or indirect genetic interactions between GDF-9 and BMP-15, we have generated double mutant mice lacking one or both alleles of these related homologs. Double homozygote females (Bmp15(-/-)Gdf9(-/-)) display oocyte loss and cysts and resemble Gdf9(-/-) mutants. In contrast, Bmp15(-/-)Gdf9(+/-) female mice have more severe fertility defects than Bmp15(-/-) females, which appear to be due to abnormalities in ovarian folliculogenesis, cumulus cell physiology, and fertilization. Thus, the dosage of intact Bmp15 and Gdf9 alleles directly influences the destiny of the oocyte during folliculogenesis and in the periovulatory period. These studies have important implications for human fertility control and the maintenance of fertility and normal ovarian physiology.