Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility
Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility
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DOI：
10.1172/jci90031
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发表时间：
2017-03-01
影响因子：
15.9
通讯作者：
Stoffel, Markus
中科院分区：
文献类型：
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作者：
Ahmed, Kashan;LaPierre, Mary P.;Stoffel, Markus
MicroRNAs(MiRNAs)是基因表达的负调控因子，可以微调许多生物过程。MiRNA功能丧失很少导致高渗透性表型，而是影响细胞对生理和病理生理应激的反应。在这里，我们已经报道了进化上保守的miR-7家族中的一个成员miR7a2，对于成年后正常的垂体发育和下丘脑-垂体-性腺(HPG)功能是必不可少的。Mir-7a2基因缺失会导致不育，导致雄性和雌性小鼠的性腺激素和性类固醇激素水平降低，睾丸或卵巢变小，精子生成受损，以及缺乏排卵。我们发现miR-7a2在垂体中高表达，它抑制高尔基体糖蛋白1(GLG1)的表达和下游的骨形态发生蛋白4(BMP4)信号，并减少前列腺素F2a受体负调节因子(PTGFRN)的表达，PTGFRN是前列腺素信号转导和卵泡刺激素(FSH)和黄体生成素(LH)分泌的抑制因子。我们的结果表明，miR-7a2通过相互连接miR-7基因组电路来调节性成熟和生殖功能，这些基因组电路通过影响垂体前列腺素和BMP4信号来调节FSH和LH的合成和分泌。
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, miR7a2, 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.