Hsieh Minnie, Lee Daekee, Panigone Sara, Horner Kathleen, Chen Ruby, Theologis Alekos, Lee David C, Threadgill David W, Conti Marco
Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5317, USA.
Mol Cell Biol. 2007 Mar;27(5):1914-24. doi: 10.1128/MCB.01919-06. Epub 2006 Dec 28.
In the preovulatory ovarian follicle, mammalian oocytes are maintained in prophase meiotic arrest until the luteinizing hormone (LH) surge induces reentry into the first meiotic division. Dramatic changes in the somatic cells surrounding the oocytes and in the follicular wall are also induced by LH and are necessary for ovulation. Here, we provide genetic evidence that LH-dependent transactivation of the epidermal growth factor receptor (EGFR) is indispensable for oocyte reentry into the meiotic cell cycle, for the synthesis of the extracellular matrix surrounding the oocyte that causes cumulus expansion, and for follicle rupture in vivo. Mice deficient in either amphiregulin or epiregulin, two EGFR ligands, display delayed or reduced oocyte maturation and cumulus expansion. In compound-mutant mice in which loss of one EGFR ligand is associated with decreased signaling from a hypomorphic allele of the EGFR, LH no longer signals oocyte meiotic resumption. Moreover, induction of genes involved in cumulus expansion and follicle rupture is compromised in these mice, resulting in impaired ovulation. Thus, these studies demonstrate that LH induction of epidermal growth factor-like growth factors and EGFR transactivation are essential for the regulation of a critical physiological process such as ovulation and provide new strategies for manipulation of fertility.
在排卵前的卵巢卵泡中，哺乳动物卵母细胞维持在减数分裂前期停滞状态，直到促黄体生成素（LH）激增诱导其重新进入第一次减数分裂。LH还会诱导卵母细胞周围的体细胞和卵泡壁发生显著变化，这些变化是排卵所必需的。在这里，我们提供了遗传学证据，表明表皮生长因子受体（EGFR）的LH依赖性反式激活对于卵母细胞重新进入减数分裂细胞周期、合成导致卵丘扩展的卵母细胞周围细胞外基质以及体内卵泡破裂是不可或缺的。缺乏双调蛋白或上皮调节蛋白这两种EGFR配体的小鼠，其卵母细胞成熟和卵丘扩展延迟或减少。在复合突变小鼠中，一种EGFR配体的缺失与EGFR次等位基因信号传导减少相关，LH不再能引发卵母细胞减数分裂恢复。此外，这些小鼠中参与卵丘扩展和卵泡破裂的基因诱导受到损害，导致排卵受损。因此，这些研究表明，LH诱导表皮生长因子样生长因子和EGFR反式激活对于排卵等关键生理过程的调节至关重要，并为操纵生育能力提供了新策略。
