Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106-4965, USA.
Biol Reprod. 2012 Aug 23;87(2):41. doi: 10.1095/biolreprod.111.097527. Print 2012 Aug.
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.
激活素是一种成熟的男性和女性生殖调节剂，可刺激卵泡刺激素的合成和分泌。尽管这种生长因子在几种生殖组织中的旁分泌作用尚未得到很好的理解，但已有报道称激活素有非垂体作用。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，我们生产了转基因组小鼠，该组小鼠在乳腺肿瘤病毒（MMTV）启动子的控制下过度表达卵泡抑素（FST），这是激活素的内在抑制剂。尽管 MMTV-Fst 小鼠是为了评估激活素在雌性中的作用而构建的，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 只转基因此前雄性都表现出交配行为并在雌性中产生阴道栓，但只有一只产生了活后代。相比之下，转基因此前雌性具有生育能力，从而允许了转基因小鼠系的扩展。对转基因此前睾丸和附睾的光镜和透射电镜检查显示，在输出管和附睾的起始段中，流体吸收和精子转运受损，这表现为流体和精子停滞的积聚。因此，在曲细精管上皮中观察到各种退行性病变，例如空泡形成和早期矿化和纤维化阶段。从 MMTV-Fst 前雄性的尾侧附睾中收集的精子头部脱落且不动。综上所述，这些数据表明激活素信号对于正常睾丸输出管功能是必需的，而其阻断会损害生育能力。这些结果还表明，激活素信号的选择性抑制剂可能为开发男性避孕药提供一种有用的方法，而不会损害雄激素的合成和作用。
