title: Neurokinin B Exerts Direct Effects on the Ovary to Stimulate Estradiol Production.
abstract: Neurokinin B (NKB) and its receptor, NK3R, play critical roles in reproduction by regulating the secretion of the hypothalamic GnRH. NKB and NK3R genes are also expressed in the ovary; however, their physiological roles within the ovary are unknown. The aim of this study was to determine whether NKB acts directly on the ovary to regulate reproduction. Injection of NKB into zebrafish accelerated follicle development, increased the mRNA levels of cyp11a1 and cyp19a1, and enhanced estradiol production. Similarly, NKB induced cyp11a1 and cyp19a1 expression in primary cultures of zebrafish follicular cells and stimulated estradiol production from cultured follicles. Furthermore, NKB activates cAMP response element-binding protein and ERK, and ERK inhibitors abolished the effect of NKB on cyp11a1, whereas protein kinase A and calmodulin-dependent protein kinase II inhibitors that blocked the activation of cAMP response element-binding protein, attenuated the effect of NKB on cyp19a1 expression. In a human granulosa cell line, COV434, a NKB agonist, senktide, also increased CYP11A1 and CYP19A1 mRNA levels and enhanced aromatase protein levels and activities. Small interfering RNA-mediated knockdown of NK3R reduced senktide-induced CYP11A1 and CYP19A1 mRNA levels. Finally, we found that NK3R mRNA was strongly down-regulated in granulosa cells obtained from polycystic ovary syndrome (PCOS) patients when compared with non-PCOS subjects. Taken together, our findings establish a direct action of NKB to induce ovarian estrogen production and raise the possibility that defective signaling of this pathway may contribute to the development of PCOS.
authors: Department of Biology (X.Q., M.S., W.Z., G.Y., C.P.), York University, Toronto, Ontario, Canada M3J 1P3; and Follicle Biology Laboratory (M.S.S., J.S.), Free University of Brussels Vrije Universiteit Brussel, 1090 Brussel, Belgium.
authors: Xin
authors: X
authors: Qi
authors: Department of Biology (X.Q., M.S., W.Z., G.Y., C.P.), York University, Toronto, Ontario, Canada M3J 1P3; and Follicle Biology Laboratory (M.S.S., J.S.), Free University of Brussels Vrije Universiteit Brussel, 1090 Brussel, Belgium.
authors: Mohamed
authors: M
authors: Salem
authors: Department of Biology (X.Q., M.S., W.Z., G.Y., C.P.), York University, Toronto, Ontario, Canada M3J 1P3; and Follicle Biology Laboratory (M.S.S., J.S.), Free University of Brussels Vrije Universiteit Brussel, 1090 Brussel, Belgium.
authors: Wenyi
authors: W
authors: Zhou
authors: Department of Biology (X.Q., M.S., W.Z., G.Y., C.P.), York University, Toronto, Ontario, Canada M3J 1P3; and Follicle Biology Laboratory (M.S.S., J.S.), Free University of Brussels Vrije Universiteit Brussel, 1090 Brussel, Belgium.
authors: Miwa
authors: M
authors: Sato-Shimizu
authors: Department of Biology (X.Q., M.S., W.Z., G.Y., C.P.), York University, Toronto, Ontario, Canada M3J 1P3; and Follicle Biology Laboratory (M.S.S., J.S.), Free University of Brussels Vrije Universiteit Brussel, 1090 Brussel, Belgium.
authors: Gang
authors: G
authors: Ye
authors: Department of Biology (X.Q., M.S., W.Z., G.Y., C.P.), York University, Toronto, Ontario, Canada M3J 1P3; and Follicle Biology Laboratory (M.S.S., J.S.), Free University of Brussels Vrije Universiteit Brussel, 1090 Brussel, Belgium.
authors: Johan
authors: J
authors: Smitz
authors: Department of Biology (X.Q., M.S., W.Z., G.Y., C.P.), York University, Toronto, Ontario, Canada M3J 1P3; and Follicle Biology Laboratory (M.S.S., J.S.), Free University of Brussels Vrije Universiteit Brussel, 1090 Brussel, Belgium.
authors: Chun
authors: C
authors: Peng
mesh_terms: D000818:Animals; D001141:Aromatase / Q000378:metabolism; D045744:Cell Line, Tumor; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism; D015536:Down-Regulation; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D015287:Neurokinin B / Q000502:physiology*; D010053:Ovary / Q000502:physiology*; D011085:Polycystic Ovary Syndrome / Q000209:etiology / Q000378:metabolism*; D018042:Receptors, Neurokinin-3 / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D018042:Receptors, Neurokinin-3; C000601381:TACR3 protein, human; D004958:Estradiol; D015287:Neurokinin B; D001141:Aromatase; C561410:CYP19A1 protein, human; D002786:Cholesterol Side-Chain Cleavage Enzyme