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.

在脊椎动物中，卵泡发生和排卵由两种不同的垂体促性腺激素调节：卵泡刺激素 (FSH) 和黄体生成素 (LH)。目前，有一个有趣的共识，即单一的下丘脑神经激素促性腺激素释放激素 (GnRH) 调节 FSH 和 LH 的分泌，尽管 FSH 和 LH 所需的时间和功能不同。然而，最近对许多非哺乳动物脊椎动物的研究表明，GnRH 对于 FSH 功能来说是可有可无的。在这里，通过使用青鳉作为硬骨鱼模型，我们成功地将胆囊收缩素鉴定为另一种促性腺激素调节剂——促卵泡激素释放激素（FSH-RH）。我们的组织学和体外分析表明，下丘脑表达胆囊收缩素的神经元通过胆囊收缩素受体 Cck2rb 直接影响 FSH 细胞，从而增加 FSH 的表达和释放。值得注意的是，该途径的敲除会最大限度地减少 FSH 表达并导致卵泡发生失败。在这里，我们提出在利用 FSH-RH 和 LH-RH 的脊椎动物中存在“双 GnRH 模型”。