Kumar T R, Varani S, Wreford N G, Telfer N M, de Kretser D M, Matzuk M M
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Endocrinology. 2001 Aug;142(8):3512-8. doi: 10.1210/endo.142.8.8336.
Activins are known to signal through two serine/threonine kinase type II receptors. Activin receptor IIA is widely expressed in the male reproductive axis, including the pituitary and testis. Our previous studies using gene knockout mice have confirmed the essential in vivo role of activin receptor IIA in FSH homeostasis. Activin receptor IIA-null male mice are fertile, have suppressed pituitary and serum FSH levels, and demonstrate a decrease in testis size as a result of reduced Sertoli cells and germ cells. Similarly, FSHbeta null male mice are fertile despite reduced testis size and Sertoli cell number. To define the direct roles of activin receptor IIA signaling locally in the testis, independent of its effects on FSH homeostasis, we generated double mutant mice lacking both activin receptor IIA and FSH by a genetic intercross and analyzed the male reproductive phenotypes. The double mutant male mice lacking both FSH and activin receptor IIA are fertile, demonstrate no significant reduction in testis size, and produce small litters compared with mice lacking either FSH or activin receptor IIA alone. Histological analyses of the testes from double mutant mice revealed the presence of normal stages of spermatogenesis. However, there was a significant reduction in the epididymal sperm number compared with that of the individual mutants. Northern blot analyses of total RNA from testes of double mutants did not reveal transcriptional up-regulation of activin receptor IIB, the other activin type II receptor. Although RNA expression profiles of many testis cell-specific markers are unaltered, stereological analysis of the testes from double mutants indicates that there was a reduction in type A and I spermatogonial number compared with that observed in individual mutants. Our results provide in vivo genetic evidence to demonstrate that activin receptor IIA signaling plays an important local role within the testis, independent of its actions via FSH homeostasis in the pituitary.
已知激活素通过两种II型丝氨酸/苏氨酸激酶受体进行信号传导。激活素受体IIA在雄性生殖轴中广泛表达，包括垂体和睾丸。我们之前使用基因敲除小鼠的研究已经证实激活素受体IIA在体内对促卵泡激素（FSH）稳态具有重要作用。缺乏激活素受体IIA的雄性小鼠可育，垂体和血清FSH水平受到抑制，并且由于支持细胞和生殖细胞数量减少，睾丸体积减小。同样，尽管睾丸体积减小且支持细胞数量减少，FSHβ基因敲除的雄性小鼠仍可育。为了确定激活素受体IIA信号在睾丸局部的直接作用，而不考虑其对FSH稳态的影响，我们通过遗传杂交产生了同时缺乏激活素受体IIA和FSH的双突变小鼠，并分析了雄性生殖表型。同时缺乏FSH和激活素受体IIA的双突变雄性小鼠可育，睾丸体积没有显著减小，与单独缺乏FSH或激活素受体IIA的小鼠相比，产仔数较少。对双突变小鼠睾丸的组织学分析显示存在正常的精子发生阶段。然而，与单个突变体相比，附睾精子数量显著减少。对双突变体睾丸总RNA的Northern印迹分析未显示另一种激活素II型受体激活素受体IIB的转录上调。尽管许多睾丸细胞特异性标志物的RNA表达谱未改变，但对双突变体睾丸的体视学分析表明，与单个突变体相比，A型和I型精原细胞数量减少。我们的结果提供了体内遗传学证据，证明激活素受体IIA信号在睾丸内发挥重要的局部作用，独立于其通过垂体中FSH稳态的作用。
