Lgr4 gene regulates corpus luteum maturation through modulation of the WNT-mediated EGFR-ERK signaling pathway. Academic Article uri icon


  • Luteal-phase insufficiency is one of the major causes of female infertility, but the molecular mechanisms are still largely unknown. Here we found that disruption of Lgr4/Gpr48, the newly identified receptor for R-spondins, greatly reduced female fertility in mice. The expression of Lgr4 was induced specifically in granulosa-lutein cells during luteinization. In Lgr4-deficient female mice, the estrous cycle was prolonged and serum progesterone levels were dramatically downregulated. In Lgr4(-/-) corpora lutea, the expression of key enzymes for steroidogenesis as well as common luteal marker genes was significantly decreased. Additionally, the activity of epidermal growth factor receptor (EGFR)-ERK signaling was attenuated in Lgr4(-/-) granulosa-lutein cells. We found that the maturation of Lgr4(-/-) cells was impaired in cultured primary granulosa cells, but the defect was partially rescued by reactivation of EGFR signaling by heparin-binding EGF-like growth factor treatment. We found that the expression of wingless-type MMTV integration site family (WNT)/catenin (cadherin associated protein), beta 1 (CTNNB1) downstream targets, including matrix metalloproteinase 9, which is a critical matrix metalloproteinase for activation of EGF-like factors, was significantly downregulated in Lgr4(-/-) ovaries. Matrix metalloproteinase 9 inhibitor treatment attenuated human chorionic gonadotropin- but not heparin-binding EGF-like growth factor-induced ERK activation and luteinization in primary granulosa cells. Together, we report that Lgr4 modulates WNT-mediated EGFR-ERK signaling to facilitate corpus luteum maturation and ovarian steroidogenesis to maintain female reproduction.

published proceedings

  • Endocrinology

altmetric score

  • 1

author list (cited authors)

  • Pan, H., Cui, H., Liu, S., Qian, Y. u., Wu, H., Li, L., ... Li, D.

citation count

  • 29

complete list of authors

  • Pan, Hongjie||Cui, Hengxiang||Liu, Shijie||Qian, Yu||Wu, Haili||Li, Liang||Guan, Yuting||Guan, Xin||Zhang, Long||Fan, Heng-Yu||Ma, Yanlin||Li, Runsheng||Liu, Mingyao||Li, Dali

publication date

  • September 2014