Granulosa cell-specific inactivation of follistatin causes female fertility defects
Granulosa cell-specific inactivation of follistatin causes female fertility defects
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DOI：
10.1210/me.2003-0301
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发表时间：
2004-04-01
影响因子：
--
通讯作者：
Matzuk, MM
中科院分区：
文献类型：
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作者：
Jorgez, CJ;Klysik, M;Matzuk, MM
卵泡抑素通过阻断激活素的作用调节FSH水平，在女性生理中发挥重要作用。FSH调节失败被认为是卵巢早衰的潜在原因。卵巢早衰的特征是闭经、不孕和40岁以下女性促性腺激素水平升高。由于卵泡抑素是必不可少的出生后的生存能力，我们设计了一个cre/loxP条件敲除系统，使卵泡抑素基因无效，特别是在出生后的卵巢颗粒细胞使用Amhr 2cre转基因小鼠。卵泡抑素条件性基因敲除的雌性会出现生育缺陷，包括窝仔数和窝仔数减少，在最严重的情况下，会出现不育。在这些小鼠中观察到卵泡数量减少、排卵和受精缺陷、血清FSH和LH水平升高以及睾酮水平降低。这些结果表明，损害颗粒细胞卵泡抑素功能导致的结果类似于卵巢早衰的特点。因此，卵泡抑素条件性基因敲除可能是一个有用的模型，以进一步研究这种人类综合征。这些研究是第一次报告的颗粒细胞特异性基因缺失在出生后的卵巢和未来的努力，以产生卵巢特异性基因敲除小鼠模型具有重要意义。
Follistatin plays an important role in female physiology by regulating FSH levels through blocking activin actions. Failure to regulate FSH has been implicated as a potential cause of premature ovarian failure. Premature ovarian failure is characterized by amenorrhea, infertility, and elevated gonadotropin levels in women under the age of 40. Because follistatin is essential for postnatal viability, we designed a cre/loxP conditional knockout system to render the follistatin gene null specifically in the granulosa cells of the postnatal ovary using Amhr2cre transgenic mice. The follistatin conditional knockout females develop fertility defects, including reduced litter number and litter sizes and, in the most severe case, infertility. Reduced numbers of ovarian follicles, ovulation and fertilization defects, elevated levels of serum FSH and LH, and reduced levels of testosterone were observed in these mice. These findings demonstrate that compromising granulosa cell follistatin function leads to findings similar to those characterized in premature ovarian failure. Follistatin conditional knockouts may therefore be a useful model with which to further study this human syndrome. These studies are the first report of a granulosa cell-specific deletion of a gene in the postnatal ovary and have important implications for future endeavors to generate ovary-specific knockout mouse models.