MSI2 in the dentate gyrus and ovary regulates the reproductive endocrine homeostasis of female mice

Musashi2 (MSI2) plays a crucial role in neural stem cells and reproductive regulation, yet its mechanism in integrating the neuro-endocrine system remains poorly understood. This study investigates how MSI2 influences ovarian function by using conditional knockout mice for Msi2 in the brain and ovary. Our results show that KRT14/MSI2 neurons in the dentate gyrus (DG) of the hippocampus directly project to the ovary. Deletion of Msi2 in the DG and ovary increases follicle number and litter size, but causes a decline in fertility and follicle reserve after 6 months of age. AAV-mediated specific knockout of Msi2 in the DG raises follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels, upregulates Hsd3b1 and Star expression in the ovary, and decreases Cyp17a1 expression, with a synergistic effect observed in DG and ovary double-knockout mice. Chemogenetic activation of the locus coeruleus (LC) → DG circuit inhibits FSH/LH secretion and reduces reproductive capacity. These findings highlight the critical role of MSI2 in regulating steroid synthesis and gonadotropin secretion through the DG→ovary axis, with its deletion leading to reproductive aging in an early reproductive enhancement followed by accelerated depletion pattern. This provides a potential strategy for targeting neuro-endocrine interactions to intervene in reproductive diseases.