title: CNP/NPR2 signaling maintains oocyte meiotic arrest in early antral follicles and is suppressed by EGFR-mediated signaling in preovulatory follicles.
abstract: Oocyte meiosis is arrested at prophase I by factors secreted from surrounding somatic cells after oocytes acquire meiotic competence at an early antral stage, and meiosis resumes in preovulatory follicles as a result of the luteinizing hormone (LH) surge. Recently, signaling by C-type natriuretic peptide (CNP) through its receptor, natriuretic peptide receptor 2 (NPR2), was found to be essential for meiotic arrest at the late antral stage. Whether or not CNP/NPR2 signaling maintains oocyte meiotic arrest in earlier follicular stages and how it is associated with meiotic resumption induced by the LH surge is unclear. In this study, we examined the expression of Nppc and Npr2, respectively encoding CNP and NPR2, in the ovaries of immature mice. Nppc and Npr2 mRNA were specifically expressed in the outer and inner granulosa cell layers, respectively, in early antral follicles. Histological analysis of mice with a mutation in Npr2 revealed precocious resumption of oocyte meiosis in early antral follicles. Ovaries of mice treated with excess human chorionic gonadotropin (hCG) exhibited markedly decreased Nppc mRNA levels in granulosa cells of preovulatory follicles. Moreover, we found that amphiregulin, a mediator of LH/hCG activity through epidermal growth factor receptor (EGFR), suppressed Nppc mRNA levels in cultured granulosa cells. These results suggest that CNP/NPR2 signaling is essential for oocyte meiotic arrest in early antral follicles and that activated LH/amphiregulin/EGFR signaling pathway suppresses this signal by downregulating Nppc expression.
authors.affiliation: Graduate School of Environmental and Life Science, Okayama University, Okayama, Japan. takehito@cc.okayama-u.ac.jp
authors.forename: Takehito
authors.initials: T
authors.lastname: Tsuji
authors.forename: Chiyo
authors.initials: C
authors.lastname: Kiyosu
authors.forename: Kouyou
authors.initials: K
authors.lastname: Akiyama
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kunieda
mesh_terms: D066258:Amphiregulin; D000818:Animals; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006062:Gonadotropins / Q000494:pharmacology; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007986:Luteinizing Hormone / Q000378:metabolism; D008540:Meiosis / Q000187:drug effects; D049469:Meiotic Prophase I; D051379:Mice; D008810:Mice, Inbred C57BL; D020098:Natriuretic Peptide, C-Type / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D006080:Ovarian Follicle / Q000378:metabolism* / Q000502:physiology; D010060:Ovulation / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D017461:Receptors, Atrial Natriuretic Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000099242:Atrial Natriuretic Factor Receptor B
chemical_list: D066258:Amphiregulin; D006063:Chorionic Gonadotropin; D066255:EGF Family of Proteins; D066246:ErbB Receptors; D006023:Glycoproteins; D006062:Gonadotropins; D036341:Intercellular Signaling Peptides and Proteins; D007986:Luteinizing Hormone; D020098:Natriuretic Peptide, C-Type; D012333:RNA, Messenger; D017461:Receptors, Atrial Natriuretic Factor; D000099242:Atrial Natriuretic Factor Receptor B; C587848:AREG protein, human; C587849:Areg protein, mouse; C541485:EGFR protein, mouse