Ovarian tachykinin signaling system induces the growth of secondary follicles during the gonadotropin-independent process.

Mammalian follicle growth development is mainly regulated by the hypothalamus-pituitary-gonadal (HPG) axis after puberty. Although pituitary hormones, gonadotropins, are involved in HPG axis signaling, they are not responsible for the growth of early-stage follicles, namely, primordial follicles, primary follicles, and secondary follicles, in both sexually immature and mature individuals. Unlike those of gonadotropin-dependent follicle growth, the specific regulatory factors of gonadotropin-independent follicle growth have yet to be identified. Here, we identified tachykinins (TKs) as inducers of gonadotropin-independent secondary follicle growth. TKs play various roles as neuropeptides or hormones in a wide variety of biological events both in the central nervous system and in peripheral tissues, but a direct effect of TKs on ovarian follicles has yet to investigated. Follicle development was suppressed in sexually immature 3-week-old knockout mice of Tac1 gene encoding TKs (substance P and neurokinin A), which is independent of gonadotropins. TKs and their receptors are specifically localized to granulosa cells in mouse secondary follicles. Furthermore, TKs upregulate the prostaglandin (PG) synthase COX-2 via the JAK1-STAT3 signaling cascade. We also demonstrated that PGE2 and PGF2α are major PGs in the immature ovary, and the secondary follicle growth was enhanced by interaction between PGE2 / PGF2α and their receptors, PGE2 receptor (EP2) localized in the oocyte membrane and PGF2α receptor (FP) localized in the oocyte membrane, the granulosa cells, and theca cells. Consequently, this study paves the way for exploring gonadotropin-independent early-stage follicle growth systems and relevant dysfunctions, including pediatric endocrinological diseases.