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首页> 外文期刊>Molecular and Cellular Biology >Hypogonadism Associated with Cyp19a1 (Aromatase) Posttranscriptional Upregulation in Celf1 Knockout Mice
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Hypogonadism Associated with Cyp19a1 (Aromatase) Posttranscriptional Upregulation in Celf1 Knockout Mice

机译：与Cyp19a1（芳香酶）Celf1基因敲除小鼠转录后上调相关的性腺功能减退。

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CELF1 is a multifunctional RNA-binding protein that controls several aspects of RNA fate. The targeted disruption of the Celf1 gene in mice causes male infertility due to impaired spermiogenesis, the postmeiotic differentiation of male gametes. Here, we investigated the molecular reasons that underlie this testicular phenotype. By measuring sex hormone levels, we detected low concentrations of testosterone in Celf1-null mice. We investigated the effect of Celf1 disruption on the expression levels of steroidogenic enzyme genes, and we observed that Cyp19a1 was upregulated. Cyp19a1 encodes aromatase, which transforms testosterone into estradiol. Administration of testosterone or the aromatase inhibitor letrozole partly rescued the spermiogenesis defects, indicating that a lack of testosterone associated with excessive aromatase contributes to the testicular phenotype. In vivo and in vitro interaction assays demonstrated that CELF1 binds to Cyp19a1 mRNA, and reporter assays supported the conclusion that CELF1 directly represses Cyp19a1 translation. We conclude that CELF1 downregulates Cyp19a1 (Aromatase) posttranscriptionally to achieve high concentrations of testosterone compatible with spermiogenesis completion. We discuss the implications of these findings with respect to reproductive defects in men, including patients suffering from isolated hypogonadotropic hypogonadism and myotonic dystrophy type I.
机译：CELF1是一种多功能的RNA结合蛋白，可控制RNA命运的几个方面。小鼠 Celf1 基因的定向破坏会因精子发生受损（雄配子减数分裂后的分化）而导致男性不育。在这里，我们调查了睾丸表型背后的分子原因。通过测量性激素水平，我们在 Celf1 -null小鼠中检测到了低浓度的睾丸激素。我们研究了 Celf1 破坏对类固醇生成酶基因表达水平的影响，并观察到 Cyp19a1 被上调。 Cyp19a1 编码芳香酶，将睾丸激素转化为雌二醇。睾丸激素或芳香化酶抑制剂来曲唑的给药可部分挽救精子发生缺陷，表明缺乏与过量芳香化酶相关的睾丸激素有助于睾丸表型。 体内和体外相互作用试验证明CELF1与 Cyp19a1 mRNA结合，而报道分子试验则支持CELF1直接抑制 Cyp19a1的结论。 翻译。我们得出结论，CELF1在转录后下调 Cyp19a1 （芳香酶），以达到与精子发生完成相容的高浓度睾丸激素。我们讨论了这些发现对男性生殖缺陷的影响，包括患有孤立性促性腺激素性性腺功能减退症和I型强直性营养不良的患者。

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