title: Ephrin-A5 Is Required for Optimal Fertility and a Complete Ovulatory Response to Gonadotropins in the Female Mouse.
abstract: Follicle growth and ovulation involve the coordinated expression of many genes, driven by FSH and LH. Reports indicate that Eph receptors and ephrins are expressed in the ovary, suggesting roles in follicle growth and/or ovulation. We previously reported FSH-induced expression of ephrin-A5 (EFNA5) and 4 of its cognate Eph receptors in mouse granulosa cells. We now report that female mice lacking EFNA5 are subfertile, exhibit a compromised response to LH, and display abnormal ovarian histology after superovulation. Efna5(-/-) females litters were 40% smaller than controls, although no difference in litter frequency was detected. The ovarian response to superovulation was also compromised in Efna5(-/-) females, with 37% fewer oocytes ovulated than controls. These results corresponded with a reduction in ovarian mRNA levels of several LH-responsive genes, including Pgr, Ptgs2, Tnfaip6, Ereg, Btc, and Adamts4, suggesting that Efna5(-/-) ovaries exhibit a partially attenuated response to LH. Histopathological analysis indicated that superovulated Efna5(-/-) females exhibited numerous ovarian defects, including intraovarian release of cumulus oocyte complexes, increased incidence of oocytes trapped within luteinized follicles, granulosa cell and follicular fluid emboli, fibrin thrombi, and interstitial hemorrhage. In addition, adult Efna5(-/-) ovaries exhibited a 4-fold increase in multioocyte follicles compared with controls, although no difference was detected in 3-week-old mice, suggesting the possibility of follicle merging. Our observations indicate that loss of EFNA5 in female mice results in subfertility and imply that Eph-ephrin signaling may also play a previously unidentified role in the regulation of fertility in women.
authors.affiliation: Department of Biochemistry (A.V.B., B.M.W., B.J.D.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 3K7; Children's Health Research Institute (A.V.B., B.M.W., B.J.D.), Lawson Health Research Institute, London, Ontario, Canada N6C 2V5; Department of Chemical Biology (A.I.S., R.Z.), Susan Lehman-Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854; and Département de Pathologie et de Microbiologie (M.P.), Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, Québec, Canada J2S 2M2.
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Buensuceso
authors.affiliation: Department of Biochemistry (A.V.B., B.M.W., B.J.D.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 3K7; Children's Health Research Institute (A.V.B., B.M.W., B.J.D.), Lawson Health Research Institute, London, Ontario, Canada N6C 2V5; Department of Chemical Biology (A.I.S., R.Z.), Susan Lehman-Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854; and Département de Pathologie et de Microbiologie (M.P.), Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, Québec, Canada J2S 2M2.
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Son
authors.affiliation: Department of Biochemistry (A.V.B., B.M.W., B.J.D.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 3K7; Children's Health Research Institute (A.V.B., B.M.W., B.J.D.), Lawson Health Research Institute, London, Ontario, Canada N6C 2V5; Department of Chemical Biology (A.I.S., R.Z.), Susan Lehman-Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854; and Département de Pathologie et de Microbiologie (M.P.), Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, Québec, Canada J2S 2M2.
authors.forename: Renping
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry (A.V.B., B.M.W., B.J.D.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 3K7; Children's Health Research Institute (A.V.B., B.M.W., B.J.D.), Lawson Health Research Institute, London, Ontario, Canada N6C 2V5; Department of Chemical Biology (A.I.S., R.Z.), Susan Lehman-Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854; and Département de Pathologie et de Microbiologie (M.P.), Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, Québec, Canada J2S 2M2.
authors.forename: Marilène
authors.initials: M
authors.lastname: Paquet
authors.affiliation: Department of Biochemistry (A.V.B., B.M.W., B.J.D.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 3K7; Children's Health Research Institute (A.V.B., B.M.W., B.J.D.), Lawson Health Research Institute, London, Ontario, Canada N6C 2V5; Department of Chemical Biology (A.I.S., R.Z.), Susan Lehman-Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854; and Département de Pathologie et de Microbiologie (M.P.), Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, Québec, Canada J2S 2M2.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Withers
authors.affiliation: Department of Biochemistry (A.V.B., B.M.W., B.J.D.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 3K7; Children's Health Research Institute (A.V.B., B.M.W., B.J.D.), Lawson Health Research Institute, London, Ontario, Canada N6C 2V5; Department of Chemical Biology (A.I.S., R.Z.), Susan Lehman-Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854; and Département de Pathologie et de Microbiologie (M.P.), Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, Québec, Canada J2S 2M2.
authors.forename: Bonnie J
authors.initials: BJ
authors.lastname: Deroo
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071121:ADAMTS4 Protein; D000818:Animals; D066259:Betacellulin / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D003338:Corpus Luteum / Q000473:pathology; D054885:Cumulus Cells / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D036386:Ephrin-A5 / Q000235:genetics* / Q000378:metabolism; D066260:Epiregulin / Q000235:genetics / Q000378:metabolism; D005260:Female; D005298:Fertility / Q000235:genetics*; D006062:Gonadotropins; D006107:Granulosa Cells / Q000473:pathology; D007246:Infertility / Q000235:genetics; D034461:Luteinization; D051379:Mice; D018345:Mice, Knockout; D006080:Ovarian Follicle / Q000473:pathology; D010053:Ovary / Q000378:metabolism* / Q000473:pathology; D010060:Ovulation / Q000235:genetics; D011348:Procollagen N-Endopeptidase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013480:Superovulation / Q000235:genetics*
chemical_list: D066259:Betacellulin; C587852:Btc protein, mouse; D015815:Cell Adhesion Molecules; D036386:Ephrin-A5; D066260:Epiregulin; C587881:Ereg protein, mouse; D006062:Gonadotropins; D012333:RNA, Messenger; C513057:Tnfaip6 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D051722:ADAM Proteins; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603919:Adamts4 protein, mouse