Abstract：
Premature ovarian insufficiency (POI) is a clinical syndrome characterised by a decline in ovarian function in women before 40 years of age and is associated with oestradiol deficiency and a complex pathogenesis. However, the aetiology of POI is still unclear and effective preventative and treatment strategies are still lacking. Methyltransferase like 3 (METTL3) is an RNA methyltransferase that is involved in spermatogenesis, oocyte development and maturation, early embryonic development, and embryonic stem cell differentiation and formation, but its role in POI is unknown. In the present study, METTL3 deficiency in follicular theca cells was found to lead to reduced fertility in female mice, with a POI-like phenotype, and METTL3 knockout promoted ovarian inflammation. Further, a reduction in METTL3 in follicular theca cells led to a decrease in the m6A modification of pri-miR-21, which further reduced pri-miR-21 recognition and binding by DGCR8 proteins, leading to a decrease in the synthesis of mature miR-21-5p. Decrease of miR-21-5p promoted the secretion of interleukin-1β (IL-1β) from follicular theca cells. Acting in a paracrine manner, IL-1β inhibited the cAMP-PKA pathway and activated the NF-κB pathway in follicular granulosa cells. This activation increased the levels of reactive oxygen species in granulosa cells, causing disturbances in the intracellular Ca2+ balance and mitochondrial damage. These cellular events ultimately led to granulosa cell apoptosis and a decrease in oestradiol synthesis, resulting in POI development. Collectively, these findings reveal how METTL3 deficiency promotes the expression and secretion of IL-1β in theca cells, which regulates ovarian functions, and proposes a new theory for the development of POI disease.
摘要：
过早卵巢功能不全（POI）是一种临床综合征，其特征是40岁之前的女性卵巢功能下降，并与雌二醇缺乏和复杂的发病机制有关。然而,POI的病因尚不清楚,仍缺乏有效的预防和治疗策略.甲基转移酶3（METTL3）是一种参与精子发生的RNA甲基转移酶，卵母细胞发育和成熟，早期胚胎发育，胚胎干细胞的分化和形成，但它在POI中的作用是未知的。在本研究中,发现卵泡膜细胞中的METTL3缺陷会导致雌性小鼠的生育能力降低，具有类似POI的表型，METTL3基因敲除促进卵巢炎症。Further,滤泡膜细胞中METTL3的减少导致pri-miR-21的m6A修饰减少，这进一步降低了pri-miR-21被DGCR8蛋白识别和结合，导致成熟miR-21-5p合成减少。miR-21-5p的减少促进卵泡膜细胞分泌白细胞介素-1β(IL-1β)。以旁分泌的方式行事，IL-1β抑制卵泡颗粒细胞cAMP-PKA通路,激活NF-κB通路。这种激活增加了颗粒细胞中活性氧的水平，引起细胞内Ca2+平衡紊乱和线粒体损伤。这些细胞事件最终导致颗粒细胞凋亡和雌二醇合成减少，导致POI发展。总的来说，这些发现揭示了METTL3缺乏如何促进IL-1β在卵泡膜细胞中的表达和分泌，调节卵巢功能，并为POI疾病的发展提出了新的理论。
