Deletion of exon 6 of the neuronal nitric oxide synthase gene in mice results in hypogonadism and infertility.
Deletion of exon 6 of the neuronal nitric oxide synthase gene in mice results in hypogonadism and infertility.
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DOI：
10.1210/endo.143.7.8921
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发表时间：
2002-07
期刊：
影响因子：
4.8
通讯作者：
R. Gyurko;S. Leupen;Paul L Huang
中科院分区：
文献类型：
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作者：
R. Gyurko;S. Leupen;Paul L Huang
一氧化氮(NO)已被认为是生殖功能的调节剂，但目前尚不清楚生育是否需要NO。神经元型一氧化氮合酶缺陷小鼠(这里称为KN1小鼠)的第一个品系繁殖正常。然而，由于β-和γ-nNOS剪接变异体的表达，在KN1小鼠中检测到残留的神经元一氧化氮合酶(NNOS)活性。我们产生了一种新的nNOS基因敲除小鼠(KN2)，它缺乏编码nNOS的血红素结合结构域的外显子6。KN2小鼠是可存活的，但交配的纯合子不会产下小鼠，这表明要么是一方不育，要么是双方都不育。雄性KN2小鼠的性腺重量减轻，但精子数量正常。Kn2雄性不会表现出交配行为，因此当与野生型(WT)雌性一起居住时，也不会离开阴道插头。Kn2雌鼠卵巢重量减轻，组织学显示黄体数量减少。放射免疫分析显示，KN2族男性血浆FSH水平降低，而KN2型女性血浆促黄体生成素水平升高，下丘脑GnRH含量增加。实验性卵巢移植表明，中枢过程而不是卵巢过程受到nNOS的影响，因为在WT激素控制下，KN2卵巢的排卵率接近正常，而WT卵巢移植到KN2鼠体内的排卵率下降。我们观察到KN2小鼠幽门狭窄，但血浆瘦素水平正常，没有发现酮，这表明性腺功能低下不是营养不良的结果。我们得出结论，nNOS是生殖功能正常的中枢激素调节所必需的。
Nitric oxide (NO) has been recognized as a modulator in reproductive functions, but it is not clear whether NO is required for fertility. The first line of mice deficient in neuronal NO synthase (referred to herein as KN1 mice) reproduce normally. However, residual neuronal NO synthase (nNOS) activity is detected in KN1 mice due to the expression of beta- and gamma-nNOS splice variants. We generated a new line of nNOS knockout mice (KN2) lacking exon 6, which codes for the heme-binding domain of nNOS. KN2 mice are viable, but mated homozygotes do not produce litters, indicating that either one or both sexes are infertile. Male KN2 mice show decreased gonad weights, but sperm counts are normal. KN2 males do not display mating behavior, and consequently do not leave vaginal plugs when housed with wild-type (WT) females. KN2 females show decreased ovary weight, and histology reveals decreased corpus luteum counts. RIAs show that KN2 males have decreased plasma FSH, whereas KN2 females have increased levels of plasma LH and increased hypothalamic GnRH content. Experimental ovarian transplantation suggests that central, rather than ovarian, processes are influenced by nNOS, as KN2 ovaries ovulate at near-normal rates under WT hormonal control, whereas WT ovaries transplanted into KN2 mice have decreased ovulation rates. We observed pyloric stenosis in KN2 mice, but plasma leptin levels are normal, and no ketones are found, indicating that hypogonadism is not a result of malnutrition. We conclude that nNOS is required for normal central hormonal regulation of reproductive function.