School of Women's and Children's Health, Fertility and Research Centre, University of New South Wales Sydney, NSW, 2052, Australia.
School of Women's and Children's Health, Fertility and Research Centre, University of New South Wales Sydney, NSW, 2052, Australia.
Mol Cell Endocrinol. 2019 Jun 15;490:37-46. doi: 10.1016/j.mce.2019.04.003. Epub 2019 Apr 3.
Development of mammalian ovarian follicles is promoted by the combined action of endocrine cues and paracrine factors. Follicle stimulating hormone (FSH), through the action of cAMP drives follicular growth and development. The oocyte secretes powerful growth factors such as bone morphogenetic protein 15 (BMP15) to regulate granulosa cell proliferation, metabolism, steroidogenesis and differentiation through the activation of SMAD1/5/8. This study investigated the role of the cAMP signalling pathway on SMAD1/5/8 action in human granulosa cells. Cyclic AMP enhanced BMP15-induction of a SMAD1/5/8-specific BRE reporter. Moreover, in the absence of BMP ligand, cAMP also activated SMAD1/5/8-induced BRE activity. Cyclic AMP increased canonical downstream targets of BMP signalling such as inhibitor of differentiation (ID) mRNA expression. The observed effects were not mediated by secretion of BMPs as cAMP did not promote BMP ligand mRNA expression and a BMP extracellular antagonist, the BMP type II receptor ectodomain, did not affect cAMP-induced ID mRNA expression. Finally, the ERK1/2 pathway was shown to be required for the maintenance of cAMP-induced SMAD1/5/8 activity. Together our results suggest a novel and non-canonical pathway for cAMP signalling in human granulosa cells. Cyclic AMP appears to promote SMAD1/5/8 pathway activity intracellularly and has the ability to activate canonical SMAD1/5/8 downstream targets. Our results add another layer of complexity to the interactions between endocrine signalling and oocyte-secreted BMP ligands during folliculogenesis. Given the importance of both cAMP and SMAD1/5/8 pathways in follicular development, these interactions are likely required for the fine-tuning of oocyte paracrine signalling by endocrine stimuli.
哺乳动物卵泡的发育是由内分泌线索和旁分泌因子的共同作用所促进的。卵泡刺激素（FSH）通过 cAMP 的作用驱动卵泡的生长和发育。卵母细胞分泌强大的生长因子，如骨形态发生蛋白 15（BMP15），通过激活 SMAD1/5/8 来调节颗粒细胞的增殖、代谢、类固醇生成和分化。本研究探讨了 cAMP 信号通路对人颗粒细胞中 SMAD1/5/8 作用的影响。环腺苷酸增强了 BMP15 诱导的 SMAD1/5/8 特异性 BRE 报告基因的活性。此外，在没有 BMP 配体的情况下，cAMP 也激活了 SMAD1/5/8 诱导的 BRE 活性。环腺苷酸增加了 BMP 信号的典型下游靶基因，如分化抑制剂（ID）mRNA 的表达。观察到的效应不是通过 BMP 配体的分泌介导的，因为 cAMP 不促进 BMP 配体 mRNA 的表达，而且 BMP 型 II 受体外显子也不影响 cAMP 诱导的 ID mRNA 的表达。最后，ERK1/2 通路被证明是维持 cAMP 诱导的 SMAD1/5/8 活性所必需的。总之，我们的研究结果表明，在人颗粒细胞中存在一种新的非经典的 cAMP 信号通路。环腺苷酸似乎促进了 SMAD1/5/8 通路的细胞内活性，并有能力激活经典的 SMAD1/5/8 下游靶基因。我们的研究结果为卵母细胞分泌的 BMP 配体与内分泌信号在卵泡发生过程中的相互作用增添了另一层复杂性。鉴于 cAMP 和 SMAD1/5/8 途径在卵泡发育中的重要性，这些相互作用可能是内分泌刺激物精细调节卵母细胞旁分泌信号所必需的。
