PMID- 29259438 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20201001 IS - 1445-5781 (Print) IS - 1447-0578 (Electronic) IS - 1445-5781 (Linking) VI - 15 IP - 4 DP - 2016 Oct TI - Roles of epidermal growth factor (EGF)-like factor in the ovulation process. PG - 201-216 LID - 10.1007/s12522-016-0236-x [doi] AB - Luteinizing hormone (LH) surge stimulates preovulatory follicles to induce the ovulation process, including oocyte maturation, cumulus expansion, and granulosa cell luteinization. The matured oocytes surrounded by an expanded cumulus cell layer are released from follicles to the oviduct. However, LH receptors are dominantly expressed in granulosa cells, but less in cumulus cells and are not expressed in oocytes, indicating that the secondary factors expressed and secreted from LH-stimulated granulosa cells are required for the induction of the ovulation process. Prostaglandin and progesterone are well-known factors that are produced in granulosa cells and then stimulate in both granulosa and cumulus cells. The mutant mice of prostaglandin synthase (Ptgs2KO mice) or progesterone receptor (PRKO mice) revealed that the functions were essential to accomplish the ovulation process, but not to induce the ovulation process. To identify the factors initiating the transfer of the stimuli of LH surge from granulosa cells to cumulus cells, M. Conti's lab and our group performed microarray analysis of granulosa cells and identified the epidermal growth factor (EGF)-like factor, amphiregulin (AREG), epiregulin (EREG), and beta-cellulin (BTC) that act on EGF receptor (EGFR) and then induce the ERK1/2 and Ca(2+)-PLC pathways in cumulus cells. When each of the pathways was down-regulated using a pharmacological approach or gene targeting study, the induction of cumulus expansion and oocyte maturation were dramatically suppressed, indicating that both pathways are inducers of the ovulation process. However, an in vitro culture study also revealed that the EGFR-induced unphysiological activation of PKC in cumulus cells accelerated oocyte maturation with low cytostatic activity. Thus, the matured oocytes are not arrested at the metaphase II (MII) stage and then spontaneously form pronuclei. The expression of another type of EGF-like factor, neuregulin 1 (NRG1), that does not act on EGFR, but selectively binds to ErbB3 is observed in granulosa cells after the LH surge. NRG1 supports EGFR-induced ERK1/2 phosphorylation, but reduces PKC activity to physiological level in the cumulus cells, which delays the timing of meiotic maturation of oocytes to adjust the timing of ovulation. Thus, both types of EGF-like factor are rapidly induced by LH surge and then stimulate cumulus cells to control ERK1/2 and PKC pathways, which results in the release of matured oocytes with a fertilization competence. FAU - Shimada, Masayuki AU - Shimada M AD - Laboratory of Reproductive Endocrinology, Graduate School of Biosphere Science Hiroshima University Higashi-Hiroshima 739-8528 Hiroshima Japan. FAU - Umehara, Takashi AU - Umehara T AD - Laboratory of Reproductive Endocrinology, Graduate School of Biosphere Science Hiroshima University Higashi-Hiroshima 739-8528 Hiroshima Japan. FAU - Hoshino, Yumi AU - Hoshino Y AD - Laboratory of Reproductive Endocrinology, Graduate School of Biosphere Science Hiroshima University Higashi-Hiroshima 739-8528 Hiroshima Japan. LA - eng PT - Journal Article PT - Review DEP - 20160215 PL - Japan TA - Reprod Med Biol JT - Reproductive medicine and biology JID - 101213278 PMC - PMC5715866 OTO - NOTNLM OT - Cumulus cells OT - Granulosa cells OT - Oocytes OT - Progesterone OT - Prostaglandin COIS- Masayuki Shimada, Takashi Umehara and Yumi Hoshino declare that they have no conflict of interest. EDAT- 2016/02/15 00:00 MHDA- 2016/02/15 00:01 PMCR- 2016/02/15 CRDT- 2017/12/21 06:00 PHST- 2015/12/14 00:00 [received] PHST- 2016/02/01 00:00 [accepted] PHST- 2017/12/21 06:00 [entrez] PHST- 2016/02/15 00:00 [pubmed] PHST- 2016/02/15 00:01 [medline] PHST- 2016/02/15 00:00 [pmc-release] AID - RMB20201 [pii] AID - 10.1007/s12522-016-0236-x [doi] PST - epublish SO - Reprod Med Biol. 2016 Feb 15;15(4):201-216. doi: 10.1007/s12522-016-0236-x. eCollection 2016 Oct.