Identification of the FSH-RH, the other gonadotropin-releasing hormone

In vertebrates, folliculogenesis and ovulation are regulated by two distinct pituitary gonadotropins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Today, there is an intriguing consensus that a single hypothalamic neurohormone, gonadotropin-releasing hormone (GnRH), regulates the secretion of both FSH and LH, although the required timing and functions of FSH and LH are different. However, recent studies in vertebrates other than mammals indicate that the effect of GnRH on FSH is too weak to explain its regulation. Therefore, to challenge this “solo GnRH model,” we aimed to identify the other gonadotropin regulator, FSH-releasing hormone (FSH-RH), in vertebrates. Here, by using the model teleost medaka, we successfully identified cholecystokinin as the FSH-RH. Our histological and in vitro analyses demonstrated that hypothalamic cholecystokinin-expressing neurons directly affect FSH cells through the cholecystokinin receptor, Cckbr1, thereby increasing the expression and release of FSH. Remarkably, the knockout of cholecystokinin ligand or cckbr1 minimized FSH expression and resulted in a complete failure of folliculogenesis. Our results challenge the longstanding consensus of the solo GnRH model in all vertebrates; instead, we propose the existence of a “dual GnRH model” group in vertebrates that utilizes both FSH-RH and LH-RH. The discovery of the FSH-RH in vertebrates opens not only a new era in neuroendocrinology but also possible applications involving vertebrate reproduction.