Mechanisms that directly control mammalian ovarian primordial follicle (PF) growth activation and the selection of individual follicles for survival are largely unknown. Follicle cells produce factors that can act as potent inducers of cellular stress during normal function. Consistent with this, we show here that normal, untreated ovarian cells, including pre-granulosa cells of dormant PFs, express phenotype and protein markers of the activated integrated stress response (ISR), including stress-specific protein translation (phospho-Serine 51 eukaryotic initiation factor 2 α ; P-EIF2 α ), active DNA damage checkpoints, and cell cycle arrest. We further demonstrate that mRNAs upregulated in primary (growing) follicles versus arrested PFs mostly include stress-responsive upstream open reading frames (uORFs). Treatment of a granulosa cell (GC) line with the PF growth trigger tumor necrosis factor alpha results in the upregulation of a ‘stress-dependent’ translation profile. This includes further elevated P-eIF2 α and a shift of uORF-containing mRNAs to polysomes. Because the active ISR corresponds to slow follicle growth and PF arrest, we propose that repair and abrogation of ISR checkpoints (e.g. checkpoint recovery) drives the GC cell cycle and PF growth activation (PFGA). If cellular stress is elevated beyond a threshold(s) or, if damage occurs that cannot be repaired, cell and follicle death ensue, consistent with physiological atresia. These data suggest an intrinsic quality control mechanism for immature and growing follicles, where PFGA and subsequent follicle growth and survival depend causally upon ISR resolution, including DNA repair and thus the proof of genomic integrity.

中文翻译：

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正常卵泡发育过程中颗粒细胞翻译和增殖的综合应激反应控制


直接控制哺乳动物卵巢原始卵泡（PF）生长激活和个体卵泡生存选择的机制在很大程度上尚不清楚。滤泡细胞产生的因子可以在正常功能期间充当细胞应激的有效诱导剂。与此一致，我们在此表明​​，正常的、未经处理的卵巢细胞，包括休眠 PF 的前颗粒细胞，表达激活的整合应激反应 (ISR) 的表型和蛋白标记，包括应激特异性蛋白翻译（磷酸丝氨酸 51 真核细胞）起始因子 2 α ；P-EIF2 α )、活性 DNA 损伤检查点和细胞周期停滞。我们进一步证明，与停滞的 PF 相比，初级（生长中）卵泡中的 mRNA 上调主要包括应激反应性上游开放阅读框（uORF）。用 PF 生长触发肿瘤坏死因子 α 处理颗粒细胞 (GC) 系会导致“应激依赖性”翻译谱上调。这包括 P-eIF2 α 的进一步升高以及含有 uORF 的 mRNA 向多核糖体的转变。由于活跃的ISR对应于缓慢的卵泡生长和PF停滞，因此我们提出ISR检查点的修复和废除（例如检查点恢复）驱动GC细胞周期和PF生长激活（PFGA）。如果细胞应激超过阈值，或者发生无法修复的损伤，细胞和卵泡就会死亡，这与生理性闭锁一致。这些数据表明了未成熟和生长卵泡的内在质量控制机制，其中 PFGA 和随后的卵泡生长和存活因果关系取决于 ISR 分辨率，包括 DNA 修复，从而证明基因组完整性。