title: Lgr4 gene regulates corpus luteum maturation through modulation of the WNT-mediated EGFR-ERK signaling pathway.
abstract: 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.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology (H.P., H.C., S.L., Y.Q., H.W., L.L., Y.G., X.G., L.Z., M.L., D.L.), Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China; Key Laboratory of Contraceptive Drugs and Devices of National Population and Family Planning Commission (H.P., R.L.), Shanghai Institute of Planned Parenthood Research, Shanghai 200032, China; Life Science Institute (H.-Y.F.), Zhejiang University, Hangzhou 310058, China; Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research (Y.M.), Hainan Reproductive Medical Center, the Affiliated Hospital of Hainan Medical University, Haikou 570102, China; and The Institute of Biosciences and Technology (M.L.), Texas A&M University Health Science Center, Houston, Texas 77030.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Pan
authors.forename: Hengxiang
authors.initials: H
authors.lastname: Cui
authors.forename: Shijie
authors.initials: S
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Qian
authors.forename: Haili
authors.initials: H
authors.lastname: Wu
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Yuting
authors.initials: Y
authors.lastname: Guan
authors.forename: Xin
authors.initials: X
authors.lastname: Guan
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.forename: Heng-Yu
authors.initials: HY
authors.lastname: Fan
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Ma
authors.forename: Runsheng
authors.initials: R
authors.lastname: Li
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Dali
authors.initials: D
authors.lastname: Li
mesh_terms: D000818:Animals; D003338:Corpus Luteum / Q000254:growth & development* / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006107:Granulosa Cells / Q000378:metabolism; D006801:Humans; D034461:Luteinization / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C496200:LGR4 protein, mouse; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D051176:beta Catenin; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D020780:Matrix Metalloproteinase 9