Department of Histology and Embryology, Yeditepe University Faculty of Medicine, Istanbul, Turkey.
Department of Medical Biology, Yeditepe University Faculty of Medicine, Istanbul, Turkey.
J Histotechnol. 2023 Jun;46(2):80-89. doi: 10.1080/01478885.2022.2109883. Epub 2022 Aug 17.
Transforming growth factor alpha (TGFα), a member of the epidermal growth factor (EGF) family, regulates cell proliferation, differentiation, and development, and involves follicular development and viability. In ovaries, TGFα is shown localized in granulosa cells (GCs) of primary follicles, theca cells (TCs) of pre-antral, antral and pre-ovulatory follicles. TGFα overexpression in mouse mammary tumor virus (MMTV-TGFα) transgenic mice causes mammary tumor after 50 weeks. However, follicular development and preservation of the ovarian follicle reserve-mediating follicle stimulating hormone (FSH) response are unknown. Mammalian target of rapamycin (mTOR) is a key regulator for cell proliferation, growth, differentiation, and apoptosis, and important for ovarian folliculogenesis and oocyte maturation. The study aim determines TGFα overexpression during folliculogenesis via mTOR signaling pathway in ovaries from 10-, 18-, 50-, and 82-week-old MMTV-TGFα mice. Histological analysis was performed, along with western blot for mTOR, p-mTOR, P70S6K, PCNA, and Caspase-3, and quantitative RNA (qRT-PCR) for and . Developing follicles number decreased and atretic follicles number increased with aging in MMTV-TGFα mice ovary. Ovaries at 18 and 82 weeks had decreased PCNA and increased Caspase-3 protein expression levels as compared to 10-week ovaries. Protein expression levels of mTOR and p-mTOR decreased gradually from ovaries at 10-18 weeks, increased at 50 weeks and decreased again at 82 weeks. These results indicate that TGFα may be one regulator of healthy follicular development and affect signaling pathway during ovarian aging. Thus, over-expression of TGFα might lead to reduced ovarian reserve and premature ovarian insufficiency.
转化生长因子α（TGFα），表皮生长因子（EGF）家族的一员，调节细胞增殖、分化和发育，并参与卵泡发育和活力。在卵巢中，TGFα定位于初级卵泡的颗粒细胞（GCs）、窦前卵泡、窦状卵泡和早黄体期卵泡的膜细胞（TCs）。小鼠乳腺肿瘤病毒（MMTV-TGFα）转基因小鼠中 TGFα 的过表达导致 50 周后发生乳腺肿瘤。然而，卵泡发育和卵巢卵泡储备的保存——介导卵泡刺激素（FSH）反应尚不清楚。哺乳动物雷帕霉素靶蛋白（mTOR）是细胞增殖、生长、分化和凋亡的关键调节剂，对卵巢卵泡发生和卵母细胞成熟很重要。本研究旨在通过 mTOR 信号通路确定 10 周、18 周、50 周和 82 周龄 MMTV-TGFα 小鼠卵巢中 TGFα 在卵泡发生过程中的过表达。进行了组织学分析，以及 mTOR、p-mTOR、P70S6K、PCNA 和 Caspase-3 的 Western blot 分析，以及 和 的定量 RNA（qRT-PCR）分析。与 10 周龄 MMTV-TGFα 小鼠卵巢相比，随着年龄的增长，发育卵泡数量减少，闭锁卵泡数量增加。与 10 周龄卵巢相比，18 周和 82 周龄卵巢的 PCNA 蛋白表达水平降低，Caspase-3 蛋白表达水平升高。从 10-18 周龄卵巢开始，mTOR 和 p-mTOR 的蛋白表达水平逐渐降低，在 50 周时增加，然后在 82 周时再次降低。这些结果表明，TGFα 可能是健康卵泡发育的一个调节因子，并影响卵巢衰老过程中的 信号通路。因此，TGFα 的过表达可能导致卵巢储备减少和卵巢早衰。
