Investigation of subfertility in the female Nsmf knockout mouse

Erica D. Louden M.D. Ph.D. , Michael P. Dougherty M.D. , Lynn P. Chorich M.S. , Ali Eroglu Ph.D., D.V.M. , Lawrence C. Layman M.D.
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Abstract

Objective

To study if a pituitary or ovarian defect contributes to subfertility of the female Nsmf knockout (KO) mouse, an animal model of the hypogonadotropic hypogonadism gene NSMF.

Design

Analysis of hypothalamic, pituitary and ovarian gene expression at baseline, serum gonadotropin levels before and after gonadotropin-releasing hormone (GnRH) stimulation, ovarian response and implantation after superovulation, gonadotropin effects after ovariectomy, and ovarian NSMF protein expression.

Setting

University research laboratory.

Patients

None; mice were used.

Interventions

Gonadotropin-releasing hormone stimulation, superovulation, and ovariectomy in separate experiments.

Main Outcome Measures

Gene expression in the hypothalamus, pituitary, and ovary; ovarian response and implantation after superovulation; serum gonadotropins after GnRH stimulation and ovariectomy; Western blot to measure ovarian NSMF expression.

Results

We found increased hypothalamic Kiss1, Gnrh1, and Jak2 mRNA expression in female Nsmf KO vs. wild type (WT) mice. However, pituitary gonadotropin, and GnRH receptor gene expression was not affected, and serum gonadotropin levels were normal. Gonadotropins increased after ovariectomy for both groups. Baseline Kiss1, Fshr, Prkaca, Prkar1a, and Gdf9 ovarian mRNA expression was increased and Cyp19a1 expression was decreased in Nsmf KO mice, while superovulated Nsmf KO mice had reduced ovarian Kiss1r, Prkar1a, and Fshr mRNA expression, 50% less oocytes, and normal implantation. Western blot demonstrated NSMF protein expression in the ovary of WT mice.

Conclusions

Altered hypothalamic and ovarian gene expression was demonstrated in female Nsmf KO mice. It is possible that increased hypothalamic Gnrh1 and Kiss1 mRNA expression could compensate for reduced NSMF enabling a normal pituitary gonadotropin response. Impaired superovulation response, altered ovarian gene expression, and decreased number of oocytes indicate ovarian dysfunction, but a uterine factor cannot be excluded. These findings provide an anatomic basis for future mechanistic studies of subfertility in female Nsmf KO mice.

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雌性Nsmf基因敲除小鼠低生育能力的研究。
目的:研究垂体或卵巢缺陷是否导致雌性Nsmf基因敲除(KO)小鼠的低生育能力,这是一种低促性腺激素性性腺功能减退症基因Nsmf的动物模型。设计:分析基线时下丘脑、垂体和卵巢基因的表达,促性腺激素释放激素(GnRH)刺激前后的血清促性腺激素水平,超排后的卵巢反应和植入,卵巢切除后的促性腺激素作用,以及卵巢NSMF蛋白表达。设置:大学研究实验室。患者:无;使用小鼠。干预措施:促性腺激素释放激素刺激、超排和卵巢切除术。主要观察指标:下丘脑、垂体和卵巢的基因表达;超排后的卵巢反应和着床;促性腺激素释放激素刺激和卵巢切除术后的血清促性腺激素;Western印迹法测定卵巢NSMF的表达。结果:我们发现雌性Nsmf-KO小鼠与野生型(WT)小鼠相比,下丘脑Kiss1、Gnrh1和Jak2mRNA表达增加。然而,垂体促性腺激素和GnRH受体基因表达没有受到影响,血清促性腺激素水平正常。卵巢切除术后,两组的促性腺激素均增加。Nsmf-KO小鼠的基线Kiss1、Fshr、Prkaca、Prkar1a和Gdf9卵巢mRNA表达增加,Cyp19a1表达减少,而超排卵Nsmf-KO小鼠的卵巢Kiss1r、Prkar1a和Fshr mRNA表达减少,卵母细胞减少50%,植入正常。Western印迹显示NSMF蛋白在WT小鼠的卵巢中表达。结论:雌性Nsmf-KO小鼠下丘脑和卵巢基因表达发生改变。下丘脑Gnrh1和Kiss1mRNA表达的增加可能补偿NSMF的减少,从而使垂体促性腺激素反应正常。超排反应受损、卵巢基因表达改变和卵母细胞数量减少表明卵巢功能障碍,但不能排除子宫因素。这些发现为未来雌性Nsmf-KO小鼠低生育能力的机制研究提供了解剖学基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
F&S science
F&S science Endocrinology, Diabetes and Metabolism, Obstetrics, Gynecology and Women's Health, Urology
CiteScore
2.00
自引率
0.00%
发文量
0
审稿时长
51 days
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