Erythropoietin-producing hepatocellular A7 triggering ovulation indicates a potential beneficial role for polycystic ovary syndromeResearch in context
Shang Li,
Junyu Zhai,
Jiansheng Liu,
Fangfang Di,
Yun Sun,
Weiping Li,
Zi-Jiang Chen,
Yanzhi Du
Affiliations
Shang Li
Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China
Junyu Zhai
Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China
Jiansheng Liu
Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China
Fangfang Di
Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China
Yun Sun
Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China
Weiping Li
Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China
Zi-Jiang Chen
Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Shandong Provincial Key Laboratory of Reproductive Medicine, Center for Reproductive Medicine, Shandong Provincial Hospital, Shandong University, Jinan 250021, China
Yanzhi Du
Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China; Corresponding author at: 845 Lingshan Road, Shanghai 200135, China.
Background: The ovulatory dysfunction mechanisms underlying polycystic ovary syndrome (PCOS) are not completely understood. And the roles of EPHA7 and EPHA7-regulated pathway factors in the pathogenesis of anovulation remain to be elucidated. Methods: We used human granulosa cells (hGCs) of PCOS and non-PCOS patients to measure EPHA7 and other target gene expressions. We performed in vitro experiments in KGN cells to verify the molecular mechanisms. Additionally, we conducted in vivo loss- and gain-of-function studies using EPHA7 shRNA lentivirus and recombinant EPHA7-Fc protein injection to identify the ovulation effects of EPHA7. Findings: EPHA7 functions as a critically positive upstream factor for the expression of ERK1/2-mediated C/EBPβ. This protein, in turn, induced the expression of KLF4 and then ADAMTS1. Moreover, decreased abundance of EPHA7 was positively correlated with that of its downstream factors in hGCs of PCOS patients. Additionally, a 1-week functional EPHA7 shRNA lentivirus in rat ovaries contributed to decreased numbers of retrieved oocytes, and a 3-week functional lentivirus led to menstrual disorders and morphological polycystic changes in rat ovaries. More importantly, we found that EPHA7 triggered ovulation in rats, and it improved polycystic ovarian changes induced by DHEA in PCOS rats. Interpretation: Our findings demonstrate a new role of EPHA7 in PCOS, suggesting that EPHA7 is an effective target for the development of innovative medicines to induce ovulation. Fund: National Key Research and Development Program of China, National Natural Science Foundation, Shanghai Municipal Education Commission--Gaofeng Clinical Medicine, and Shanghai Commission of Science and Technology. Keywords: PCOS, Ovulation, Female fertility, EPHA7
