Cheng Yuan, Kim Jaehong, Li Xiao Xiao, Hsueh Aaron J
Program of Reproductive and Stem Cell Biology, Department of Ob/Gyn, Stanford University School of Medicine, Stanford, CA, United States of America.
PLoS One. 2015 Feb 24;10(2):e0117769. doi: 10.1371/journal.pone.0117769. eCollection 2015.
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase and mTOR signaling is important in regulating cell growth and proliferation. Recent studies using oocyte- and granulosa cell-specific deletion of mTOR inhibitor genes TSC1 or TSC2 demonstrated the important role of mTOR signaling in the promotion of ovarian follicle development. We now report that treatment of ovaries from juvenile mice with an mTOR activator MHY1485 stimulated mTOR, S6K1 and rpS6 phosphorylation. Culturing ovaries for 4 days with MHY1485 increased ovarian explant weights and follicle development. In vivo studies further demonstrated that pre-incubation of these ovaries with MHY1485 for 2 days, followed by allo-grafting into kidney capsules of adult ovariectomized hosts for 5 days, led to marked increases in graft weights and promotion of follicle development. Mature oocytes derived from MHY1485-activated ovarian grafts could be successfully fertilized, leading the delivery of healthy pups. We further treated ovaries with the mTOR activator together with AKT activators (PTEN inhibitor and phosphoinositol-3-kinase stimulator) before grafting and found additive enhancement of follicle growth. Our studies demonstrate the ability of an mTOR activator in promoting follicle growth, leading to a potential strategy to stimulate preantral follicle growth in infertile patients.
雷帕霉素哺乳动物靶点（mTOR）是一种丝氨酸/苏氨酸激酶，mTOR信号传导在调节细胞生长和增殖中起重要作用。最近利用卵母细胞和颗粒细胞特异性缺失mTOR抑制剂基因TSC1或TSC2的研究表明，mTOR信号传导在促进卵巢卵泡发育中起重要作用。我们现在报告，用mTOR激活剂MHY1485处理幼年小鼠的卵巢可刺激mTOR、S6K1和rpS6磷酸化。用MHY1485培养卵巢4天可增加卵巢外植体重量和卵泡发育。体内研究进一步表明，将这些卵巢与MHY1485预孵育2天，然后同种移植到成年去卵巢宿主的肾囊中5天，可导致移植重量显著增加并促进卵泡发育。源自MHY1485激活的卵巢移植物的成熟卵母细胞能够成功受精，从而产下健康幼崽。我们在移植前用mTOR激活剂与AKT激活剂（PTEN抑制剂和磷酸肌醇-3-激酶刺激剂）一起处理卵巢，发现卵泡生长有累加增强作用。我们的研究证明了mTOR激活剂促进卵泡生长的能力，从而为刺激不育患者的窦前卵泡生长提供了一种潜在策略。
