METTL3 deficiency leads to ovarian insufficiency due to IL-1β overexpression in theca cells.

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. A model for action of premature ovarian insufficiency due to METTL3 gene deletion in ovarian theca cells. The reduction of METTL3 in theca cells (TCs) led to a decrease in the level of m6A modification of pri-miR-21, which further reduced the recognition and binding of DGCR8 proteins to pri-miR-21, leading to a decrease in the synthesis of mature miR-21-5p, which then promoted the secretion of IL-1β from TCs. IL-1β acted in a paracrine manner on granulosa cells (GCs) by inhibiting the cAMP-PKA signalling pathway and activating the NF-κB pathway, which disrupted the intracellular Ca2+ balance, causing mitochondrial damage, which in turn led to GCs apoptosis, and at the same time affected the synthesis of estradiol, ultimately leading to the occurrence of premature ovarian insufficiency. [Display omitted] • Knockout of METTL3 in mouse TCs leads to POI. • METTL3 reduction resulted in decreased pri-miR-21 m6A modifications, thus promoted IL-1β secretion from TCs. • IL-1β induces apoptosis in GCs via the cAMP-PKA –NF–κB pathway. [ABSTRACT FROM AUTHOR]