The role of steroidogenic factor 1 (SF-1) in somatic cell function of the testes and ovaries of mature mice.
The role of steroidogenic factor 1 (SF-1) in somatic cell function of the testes and ovaries of mature mice.
复制标题
类固醇生成因子 1 (SF-1) 在成熟小鼠睾丸和卵巢体细胞功能中的作用。
DOI：
10.1530/rep-22-0049
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发表时间：
2022
期刊：
影响因子：
3.8
通讯作者：
B. Murphy
中科院分区：
文献类型：
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作者：
O. Smith;Fanny Morin;Vickie Roussel;Micka C. Bertucci;A. Boyer;B. Murphy
类固醇生成因子1(SF-1或NR5A1)在胎儿性腺发育中起重要作用，并调节类固醇生物合成相关基因。由于SF-1在小鼠性腺中表达于多种细胞类型，我们利用Cre重组酶和SF-1的等位基因Nr5a1f/f建立了三种新的条件性KO小鼠模型，以确定其在成熟小鼠睾丸和卵巢中的作用：细胞色素P45017α羟基酶(Cyp17Cre/+；Nr5a1f/f，间质和卵泡膜细胞特异性)，芳香化酶(Cyp19Cre/+；Nr5a1f/f，Sertoli和颗粒细胞特异性)，以及两者的组合(Cyp17Cre/+；Nr5a1f/f)。与对照动物相比，Cyp19-Cre；Nr5a1f/f CKO雄性小鼠具有正常的生育能力和睾丸功能。Cyp17Cre/+；Nr5a1f/f CKO雄鼠的睾丸较小，睾丸间质细胞体积显著减少，类固醇合成受损，但其生殖性能与对照组相当。大约50%的Cyp17Cre/++Cyp19Cre/+；Nr5a1f/f双CKO(DKO)男性不育，而其余50%的男性表现出显著的生育能力下降。这些dKO雄鼠的睾丸较小，有退化的生精小管，间质细胞形态异常，睾丸内睾酮水平较低。DKO睾丸支持细胞定位异常，表现为Sox9、p27和抑制素亚单位B增加，雄激素受体(AR)表达降低。尽管Cyp17Cre/+、Nr5a1f/f CKO和dKO雌性小鼠的类固醇激素基因表达水平显著降低，但所有基因型的雌性小鼠都表现出正常的生殖能力。这些结果表明，SF-1在小鼠成熟性腺类固醇生成基因的表达中起着重要作用，对睾丸间质和支持细胞的功能具有重要作用，而睾丸中所有类固醇生成细胞中SF-1的缺失影响了类固醇生成、精子发生和男性生育。
Steroidogenic factor 1 (SF-1 or NR5A1) plays an essential role in development of fetal gonads and regulates genes involved in steroid biosynthesis. Since SF-1 is expressed in multiple cell types in mouse gonads, we developed three novel conditional KO (cKO) mouse models employing Cre-recombinase and floxed alleles of SF-1 (Nr5a1f/f) to identify its role in testes and ovaries of mature mice: Cytochrome P450 17α-hydroxylase (Cyp17Cre/+;Nr5a1f/f, Leydig and theca cell specific), aromatase (Cyp19Cre/+;Nr5a1f/f, Sertoli and granulosa cell specific), as well as a combination of both (Cyp17+Cyp19-Cre;Nr5a1f/f). Compared to control animals, Cyp19-Cre;Nr5a1f/f cKO males showed normal fertility and testicular function. The Cyp17Cre/+;Nr5a1f/f cKO males had smaller testis, with drastically reduced Leydig cell volumes and impaired steroidogenesis, though their reproductive performance remained comparable to controls. Some 50 % of Cyp17Cre/++Cyp19Cre/+;Nr5a1f/f double-cKO (dKO) males were infertile, while the remaining 50 % showed significantly reduced fertility. These dKO males also had smaller testis with degenerative seminiferous tubules, abnormal Leydig cell morphology and lower levels of intra-testicular testosterone. Abnormal Sertoli cell localization was noted in dKO testes, with increased Sox9, p27 and inhibin subunit ßb and decreased androgen receptor (AR) expression. Female mice from all genotypes showed normal reproductive capacity, though steroidogenic gene expression levels were significantly decreased in both Cyp17Cre/+;Nr5a1f/f cKO and dKO females. These results show the essential role of SF-1 in mature mouse gonad steroidogenic gene expression, for Leydig and Sertoli cell function, and that depletion SF-1 in all steroidogenic cells of the testis compromises steroidogenesis, spermatogenesis, and male fertility.