Reproductive deficiencies in transgenic mice expressing the rat inhibin alpha-subunit gene.
Reproductive deficiencies in transgenic mice expressing the rat inhibin alpha-subunit gene.
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发表时间：
2001
期刊：
影响因子：
4.8
通讯作者：
B. Cho;M. L. McMullen;L. Pei;C. Yates;K. Mayo
中科院分区：
文献类型：
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作者：
B. Cho;M. L. McMullen;L. Pei;C. Yates;K. Mayo
抑制素作为性腺内的调节因子，在内分泌水平上是生殖功能的重要调节因子，它通过调节垂体FSH的生物合成，在旁分泌和自分泌水平上也是生殖功能的重要调节因子。为了研究抑制素在体内对FSH调节和性腺功能的作用，建立了高表达大鼠抑制素α亚单位基因的转基因小鼠。利用融合了小鼠金属硫蛋白-I基因启动子(MT-α)和大鼠抑制素α亚基前体编码序列的转基因小鼠，获得了三个转基因小鼠系。转基因mRNA在许多组织中表达，包括脑垂体、肝脏、睾丸、卵巢和肾脏。在转基因的垂体和卵巢中，抑制素α亚基蛋白也增加。与对照组相比，血清抑制素α亚基水平显著升高。与野生型相比，转基因卵巢中抑制素β(A)和β(B)亚单位蛋白的含量较低，尽管转基因雌性小鼠的血清激活素A水平并没有显著降低。在雄性和雌性转基因小鼠中，FSH水平都降低了，而在MT-α雌性小鼠中，黄体生成素水平升高了。MT-α转基因雌性不能生育，与野生型雌性相比，其产仔数减少了52%。MT-Alpha雌性小鼠的产仔数越小，在正常周期中排卵的数量就越少。用外源性促性腺激素处理转基因雌性动物的排卵率与受刺激的野生型动物相似，这表明促性腺激素水平的变化可能是排卵率下降的原因。尽管精子数量减少了约50%，但MT-Alpha转基因雄性小鼠具有生育能力，其雄性后代的大小与野生型雄性小鼠相同。这些结果表明，大鼠抑制素α亚单位基因在小鼠体内的过表达导致正常的抑制素/激活素比率的破坏和生殖缺陷，支持了抑制素和激活素在体内调节FSH分泌并对正常性腺功能至关重要的假说。
Inhibin is an important modulator of reproductive function at both the endocrine level, through its regulation of pituitary FSH biosynthesis, and at the paracrine and autocrine levels, as an intragonadal regulatory factor. To investigate the in vivo actions of inhibin in FSH regulation and gonadal function, transgenic mice that overexpress the rat inhibin alpha-subunit gene were generated. A transgene that includes the mouse metallothionein-I gene promoter (MT-alpha) fused to the rat inhibin alpha-subunit precursor coding sequences was used to produce three lines of transgenic mice. Transgene mRNA is expressed in numerous tissues, including the pituitary, liver, testis, ovary, and kidney. Inhibin alpha-subunit protein was also increased in transgenic pituitary and ovary. Serum inhibin alpha-subunit levels are highly increased compared with control mice. Inhibin beta(A)- and beta(B)-subunit protein amounts are lower in transgenic ovaries compared with wild type, although serum levels of activin A are not significantly reduced in transgenic female mice. FSH levels are reduced in both male and female transgenic mice, whereas LH levels are increased in MT-alpha female mice. MT-alpha transgenic females are subfertile and exhibit a 52% reduction in litter size compared with wild-type females. The smaller litter size of MT-alpha female mice was correlated with a reduction in the number of oocytes ovulated during a normal cycle. Treatment of the transgenic females with exogenous gonadotropins resulted in an ovulation rate similar to that of stimulated wild-type animals, suggesting that altered gonadotropin levels may be responsible for the decreased ovulation rates. MT-alpha transgenic male mice are fertile and sire litters of equivalent size to those sired by wild-type males, despite an approximately 50% reduction in sperm numbers. These results indicate that overexpression of the rat inhibin alpha-subunit gene in mice leads to a disruption of the normal inhibin-to-activin ratio and to reproductive deficiencies, and they support the hypothesis that inhibin and activin act to regulate FSH secretion in vivo and are essential for normal gonadal function.