Shun Kenny Uehara: Atmosphere and Ocean Research Institute, The University of Tokyo, Chiba, Japan. ORCID
Yuji Nishiike: Department of Aquatic Bioscience, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan. ORCID
Kazuki Maeda: Atmosphere and Ocean Research Institute, The University of Tokyo, Chiba, Japan.
Tomomi Karigo: Kennedy Krieger Institute, Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ORCID
Shigehiro Kuraku: Laboratory for Phyloinformatics, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan. ORCID
Kataaki Okubo: Department of Aquatic Bioscience, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan. ORCID
Shinji Kanda: Atmosphere and Ocean Research Institute, The University of Tokyo, Chiba, Japan. shinji@aori.u-tokyo.ac.jp. ORCID
In vertebrates, folliculogenesis and ovulation are regulated by two distinct pituitary gonadotropins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Currently, 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 many non-mammalian vertebrates indicated that GnRH is dispensable for FSH function. Here, by using medaka as a model teleost, we successfully identify cholecystokinin as the other gonadotropin regulator, FSH-releasing hormone (FSH-RH). Our histological and in vitro analyses demonstrate that hypothalamic cholecystokinin-expressing neurons directly affect FSH cells through the cholecystokinin receptor, Cck2rb, thereby increasing the expression and release of FSH. Remarkably, the knockout of this pathway minimizes FSH expression and results in a failure of folliculogenesis. Here, we propose the existence of the "dual GnRH model" in vertebrates that utilize both FSH-RH and LH-RH.
