Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a
Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a
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DOI：
10.1242/dev.02667
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发表时间：
2007-01-01
期刊：
影响因子：
4.6
通讯作者：
Liu, Kui
中科院分区：
文献类型：
--
作者：
Liu, Lian;Rajareddy, Singareddy;Liu, Kui
近年来，哺乳动物卵母细胞被认为在卵巢卵泡发育和生育过程中起着重要的调节作用。为了确定卵母细胞内Foxo3a（磷脂酰肌醇3-激酶（PI3K）信号通路的一个组成部分）是否影响卵泡发育和雌性生育能力，我们构建了一个在卵母细胞中表达组成型活性Foxo3a的转基因小鼠模型。我们发现雌性转基因小鼠不育，这是由于卵母细胞生长和卵泡发育迟缓和无排卵引起的。进一步的机制研究发现，在卵母细胞中具有组成性活性的Foxo3a导致骨形态发生蛋白15 （bone morphogenic protein 15, Bmp15）、连接蛋白37和连接蛋白43的表达显著降低，这些蛋白是卵泡内建立旁分泌和间隙连接通信的重要分子。Foxo3a还被发现促进卵母细胞中p27（kip1）的核定位，p27是一种细胞周期蛋白依赖性激酶（Cdk）抑制剂，可能有助于抑制卵母细胞的生长。本研究结果表明Foxo3a是一种重要的卵母细胞内信号分子，负调控卵母细胞生长和卵泡发育。因此，我们的研究可能会对人类疾病（如卵巢早衰）中导致卵泡发育和无排卵缺陷的卵母细胞遗传畸变提供一些见解。
In recent years, mammalian oocytes have been proposed to have important roles in the orchestration of ovarian follicular development and fertility. To determine whether intra-oocyte Foxo3a, a component of the phosphatidylinositol 3-kinase (PI3K) signaling pathway, influences follicular development and female fertility, a transgenic mouse model was generated with constitutively active Foxo3a expressed in oocytes. We found that the female transgenic mice were infertile, which was caused by retarded oocyte growth and follicular development, and anovulation. Further mechanistic studies revealed that the constitutively active Foxo3a in oocytes caused a dramatic reduction in the expression of bone morphogenic protein 15 (Bmp15), connexin 37 and connexin 43, which are important molecules for the establishment of paracrine and gap junction communications in follicles. Foxo3a was also found to facilitate the nuclear localization of p27(kip1) in oocytes, a cyclin-dependent kinase (Cdk) inhibitor that may serve to inhibit oocyte growth. The results from the current study indicate that Foxo3a is an important intra-oocyte signaling molecule that negatively regulates oocyte growth and follicular development. Our study may therefore give some insight into oocyte-borne genetic aberrations that cause defects in follicular development and anovulation in human diseases, such as premature ovarian failure.