Ahmed Kashan, LaPierre Mary P, Gasser Emanuel, Denzler Rémy, Yang Yinjie, Rülicke Thomas, Kero Jukka, Latreille Mathieu, Stoffel Markus
J Clin Invest. 2017 Mar 1;127(3):1061-1074. doi: 10.1172/JCI90031. Epub 2017 Feb 20.
MicroRNAs (miRNAs) are negative modulators of gene expression that fine-tune numerous biological processes. miRNA loss-of-function rarely results in highly penetrant phenotypes, but rather, influences cellular responses to physiologic and pathophysiologic stresses. Here, we have reported that a single member of the evolutionarily conserved miR-7 family, miR-7a2, is essential for normal pituitary development and hypothalamic-pituitary-gonadal (HPG) function in adulthood. Genetic deletion of mir-7a2 causes infertility, with low levels of gonadotropic and sex steroid hormones, small testes or ovaries, impaired spermatogenesis, and lack of ovulation in male and female mice, respectively. We found that miR-7a2 is highly expressed in the pituitary, where it suppresses golgi glycoprotein 1 (GLG1) expression and downstream bone morphogenetic protein 4 (BMP4) signaling and also reduces expression of the prostaglandin F2a receptor negative regulator (PTGFRN), an inhibitor of prostaglandin signaling and follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion. Our results reveal that miR-7a2 critically regulates sexual maturation and reproductive function by interconnecting miR-7 genomic circuits that regulate FSH and LH synthesis and secretion through their effects on pituitary prostaglandin and BMP4 signaling.
微小RNA（miRNA）是基因表达的负调控因子，可微调众多生物学过程。miRNA功能丧失很少导致高外显率的表型，而是影响细胞对生理和病理生理应激的反应。在此，我们报道了进化保守的miR-7家族的单个成员miR-7a2，对成年期正常垂体发育和下丘脑-垂体-性腺（HPG）功能至关重要。mir-7a2的基因缺失导致不育，促性腺激素和性类固醇激素水平低，雄性和雌性小鼠的睾丸或卵巢小，精子发生受损，以及分别缺乏排卵。我们发现miR-7a2在垂体中高度表达，在那里它抑制高尔基体糖蛋白1（GLG1）的表达和下游骨形态发生蛋白4（BMP4）信号传导，并且还降低前列腺素F2α受体负调节因子（PTGFRN）的表达，PTGFRN是前列腺素信号传导以及促卵泡激素（FSH）和促黄体生成素（LH）分泌的抑制剂。我们的结果表明，miR-7a2通过连接miR-7基因组回路来关键地调节性成熟和生殖功能，这些回路通过其对垂体前列腺素和BMP4信号传导的影响来调节FSH和LH的合成与分泌。
