title: Epiregulin-dependent amphiregulin expression and ERBB2 signaling are involved in luteinizing hormone-induced paracrine signaling pathways in mouse ovary.
abstract: Sustained EGF receptor (EGFR) phosphorylation by de novo synthesis of EGFR ligands plays an essential role in mediating luteinizing hormone (LH)-induced ovulation process in the preovulatory follicles (POFs). In the present study, the effect of epiregulin (EREG) on oocyte maturation and ovulation was investigated using Ereg knockout (Ereg-/-) mice congenic on a C57BL/6 background. Rate of spontaneous oocyte meiotic resumption of denuded oocytes (DOs) or cumulus cell-oocyte complexes (COCs) in vitro is similar between wild-type and Ereg-/- mice. However, gonadotropin-induced meiotic resumption in vivo is attenuated, and the number of COCs with expanded cumulus matrix and superovulated eggs dramatically decrease in Ereg-/- mice. Nonetheless, the number of eggs ovulated during normal estrus cycles and litter sizes in Ereg-/- mice are comparable to those of wild-type littermates. In contrast to other EGFR ligands, induction of amphiregulin (Areg) mRNA is severely reduced in ovaries collected from Ereg-/- mice either after human chorionic gonadotropin (hCG) treatment in immature mice or LH surge in adults. Gonadotropin-induced EGFR and ERBB2 phosphorylation in ovaries is attenuated in immature Ereg-/- mice, and MAPK3/1 phosphorylation and prostaglandin synthase 2 (PTGS2) protein levels are reduced. This attenuation, however, is no longer detectable in adult Ereg-/- mice after LH surge. This study implicates that EREG mediates signals downstream of Areg mRNA expression and that EGFR-ERBB2 signals contributes to regulation of ovulation process.
authors.affiliation: Department of Life Science and Pharmaceutical Science, Ewha Womans University, Seoul, South Korea.
authors.forename: Kyoungmi
authors.initials: K
authors.lastname: Kim
authors.forename: Hyunji
authors.initials: H
authors.lastname: Lee
authors.forename: David W
authors.initials: DW
authors.lastname: Threadgill
authors.forename: Daekee
authors.initials: D
authors.lastname: Lee
mesh_terms: D066258:Amphiregulin; D000818:Animals; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D066260:Epiregulin; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D007986:Luteinizing Hormone / Q000378:metabolism*; D008540:Meiosis; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010053:Ovary / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D010060:Ovulation; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D066258:Amphiregulin; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor; D066260:Epiregulin; D066246:ErbB Receptors; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D007986:Luteinizing Hormone; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C587848:AREG protein, human; C587849:Areg protein, mouse; C587880:EREG protein, human; C587881:Ereg protein, mouse; C541485:EGFR protein, mouse; C524056:Erbb2 protein, mouse