Overexpression of Follistatin in the Mouse Epididymis Disrupts Fluid Resorption and Sperm Transit in Testicular Excurrent Ducts
Overexpression of Follistatin in the Mouse Epididymis Disrupts Fluid Resorption and Sperm Transit in Testicular Excurrent Ducts
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DOI：
10.1095/biolreprod.111.097527
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发表时间：
2012-08-01
影响因子：
3.6
通讯作者：
Keri, Ruth A.
中科院分区：
文献类型：
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作者：
Seachrist, Darcie D.;Johnson, Emhonta;Keri, Ruth A.
激活素是一种成熟的男性和女性生殖调节剂，可刺激促卵泡激素的合成和分泌。激活素的非垂体作用也有报道，尽管这种生长因子在几种生殖组织中的旁分泌作用尚不清楚。为了确定激活素在乳腺形态发生和肿瘤进展过程中的旁分泌功能，我们生产了在小鼠乳腺肿瘤病毒（MMTV）启动子控制下过表达卵泡抑素（FST）的转基因小鼠，卵泡抑素是激活素的内在抑制剂。尽管构建 MMTV-Fst 小鼠是为了评估激活素在雌性小鼠中的作用，但在雄性的睾丸和附睾中也观察到了转基因的表达。虽然所有 17 只转基因雄性创始人都表现出交配行为，并在雌性身上产生了阴道塞，但只有一只产生了活的后代。相比之下，转基因雌性具有生育能力，允许转基因小鼠品系的扩展。转基因睾丸和附睾的光和透射电子显微镜检查显示，传出管和附睾初始段的液体吸收和精子转运受损，如液体积聚和精子停滞所示。因此，在生精上皮中观察到多种退行性病变，例如空泡化以及矿化和纤维化的早期阶段。从 MMTV-Fst 雄性附睾尾收集的精子头部脱落且不动。总之，这些数据表明，激活素信号传导对于正常睾丸外管功能至关重要，并且其阻断会损害生育能力。这些结果还表明，激活素信号传导的选择性抑制剂可能为男性避孕药的开发提供一种有用的方法，而不会影响雄激素的合成和作用。
Activin is a well-established modulator of male and female reproduction that stimulates the synthesis and secretion of follicle-stimulating hormone. Nonpituitary effects of activin have also been reported, although the paracrine actions of this growth factor in several reproductive tissues are not well understood. To identify the paracrine functions of activin during mammary gland morphogenesis and tumor progression, we produced transgenic mice that overexpress follistatin (FST), an intrinsic inhibitor of activin, under control of the mouse mammary tumor virus (MMTV) promoter. Although the MMTV-Fst mice were constructed to assess the role of activin in females, expression of the transgene was also observed in the testes and epididymides of males. While all 17 transgenic founder males exhibited copulatory behavior and produced vaginal plugs in females, only one produced live offspring. In contrast, transgenic females were fertile, permitting expansion of transgenic mouse lines. Light and transmission electron microscopic examination of the transgenic testes and epididymides revealed impairment of fluid resorption and sperm transit in the efferent ducts and initial segment of the epididymis, as indicated by accumulation of fluid and sperm stasis. Consequently, a variety of degenerative lesions were observed in the seminiferous epithelium, such as vacuolation and early stages of mineralization and fibrosis. Sperm collected from the caudae epididymidis of MMTV-Fst males had detached heads and were immotile. Together, these data reveal that activin signaling is essential for normal testicular excurrent duct function and that its blockade impairs fertility. These results also suggest that selective inhibitors of activin signaling may provide a useful approach for the development of male contraceptives without compromising androgen synthesis and actions.