hnRNPL modulates synapsis gene and mTOR splicing to influence primordial follicle formation and activation

The primordial follicle pool established during the perinatal period, serves as the lifelong source of oocytes, with its depletion leading to premature ovarian failure. During the process of primordial germ cell (PGC) development and the formation of primordial follicles, germ cell development is regulated by precise transcriptional control, accompanied by extensive post-transcriptional alternative splicing (AS) events. The role of AS during PGC development and follicle formation remains poorly understood. In this study, we explore AS dynamics and identify hnRNPL, a splicing regulator, as a critical factor in primordial follicle pool formation. Using a conditional knockout (cKO) model, we demonstrate that loss of hnRNPL in pre-meiotic germ cells impairs splicing of genes involved in homologous synapsis and autophagy, leading to oocyte arrest, reduced follicle pool size, and accelerated ovarian aging. Excessive autophagy exacerbates oocyte atresia, further contributing to infertility. Our findings highlight hnRNPL as a key regulator of AS in oocyte development and suggest potential therapeutic targets for rescuing fertility in cases of disrupted primordial follicle formation.