Liver receptor homolog 1 is essential for ovulation
Liver receptor homolog 1 is essential for ovulation
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DOI：
10.1101/gad.472008
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发表时间：
2008-07-15
影响因子：
10.5
通讯作者：
Schoonjans, Kristina
中科院分区：
文献类型：
--
作者：
Duggavathi, Rajesha;Volle, David H.;Schoonjans, Kristina
女性生育能力需要正常的卵巢卵泡生长和排卵。核受体肝受体同系物1（Lrh1）参与多种过程，如胆汁酸代谢、类固醇生成和细胞增殖。在卵巢中，Lrh1仅在颗粒细胞和黄体细胞中表达。通过体细胞靶向诱变，我们发现颗粒细胞中缺乏Lrh1的小鼠由于不排卵而不育。排卵前刺激无法引起这些小鼠的卵丘扩展、黄体化和卵泡破裂。多种缺陷，包括Lrh1靶基因一氧化氮合酶3的转录激活严重降低，导致在缺乏Lrh1时卵泡内雌二醇水平升高。这进一步导致前列腺素和透明质酸级联反应功能失调，并中断卵丘扩展。由于Lrh1靶基因类固醇生成急性调节蛋白和细胞色素P450侧链裂解酶的正常表达失败，缺乏Lrh1也会干扰孕酮合成。此外，排卵所必需的细胞外基质蛋白酶的表达也受到损害。这些结果表明，Lrh1是卵巢卵泡成熟和排卵所必需的多种机制的调节因子。因此，Lrh1是女性生育能力的关键调节因子，也是避孕的潜在靶点。
Female fertility requires normal ovarian follicular growth and ovulation. The nuclear receptor liver receptor homolog 1 has been implicated in processes as diverse as bile acid metabolism, steroidogenesis, and cell proliferation. In the ovary, Lrh1 is expressed exclusively in granulosa and luteal cells. Using somatic targeted mutagenesis, we show that mice lacking Lrh1 in granulosa cells are sterile, due to anovulation. The preovulatory stimulus fails to elicit cumulus expansion, luteinization, and follicular rupture in these mice. Multiple defects, including severely reduced transactivation of the Lrh1 target gene, nitric oxide synthase 3, leads to increased intrafollicular estradiol levels in the absence of Lrh1. This further causes dysfunction of prostaglandin and hyaluronic acid cascades and interrupts cumulus expansion. Lack of Lrh1 also interferes with progesterone synthesis because of failure of normal expression of the Lrh1 targets, steroidogenic acute regulatory protein and cytochrome P450 side-chain cleavage. In addition, expression of extracellular matrix proteases essential for ovulation is compromised. These results demonstrate that Lrh1 is a regulator of multiple mechanisms essential for maturation of ovarian follicles and for ovulation. Lrh1 is therefore a key modulator of female fertility and a potential target for contraception.