LH-induced neuregulin 1 (NRG1) type III transcripts control granulosa cell differentiation and oocyte maturation.
Epidermal growth factor (EGF)-like factors [amphiregulin (AREG), betacellulin, and epiregulin] are induced by LH and activate the EGF receptor (ERBB1)/ERK1/2 pathway in granulosa cells and cumulus cells of preovulatory follicles to impact ovulation. However, the expression and roles of other ERBB family members and their ligands have not been explored in detail. Herein, we document that two transcripts of the neuregulin (Nrg1) gene are expressed in granulosa cells, and that the type III Nrg1 is induced during ovulation in an ERK1/2 and C/EBPβ-dependent manner. Western blotting shows that intact (75 kDa) and secreted (45 kDa) forms of neuregulin 1 (NRG1) are present in the ovary. NRG1 likely binds to ERBB3/ERBB2 complexes that are expressed in granulosa cells and cumulus cells. In cultured granulosa cells, NRG1 selectively stimulates the phosphorylation of AKT/PKB compared to ERK1/2. However, when granulosa cells were cultured with NRG1 and AREG, the phosphorylation of ERK1/2 was markedly enhanced as compared with that by AREG alone. Cotreatment with NRG1 and AREG also increased progesterone production. When cumulus-oocyte complexes (COCs) were cultured with both NRG1 and AREG, the matured oocytes exhibited significantly higher developmental competence as compared with that of oocytes cultured with AREG alone. Collectively, these results document that the expression of type III NRG1 is induced in granulosa cells during ovulation and that NRG1 enhances AREG-induced ERK1/2 phosphorylation in both granulosa cells and cumulus cells. The NRG1 pathway has two roles: one is to enhance AREG-induced progesterone production in granulosa cells, and the other is to regulate oocyte maturation by a cumulus cell-dependent mechanism.
Laboratory of Reproductive Endocrinology, Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan.
Noritaka
N
Noma
Ikko
I
Kawashima
Heng-Yu
HY
Fan
Youko
Y
Fujita
Tomoko
T
Kawai
Yoshinori
Y
Tomoda
Toshihiro
T
Mihara
Joanne S
JS
Richards
Masayuki
M
Shimada
D066258:Amphiregulin; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D054885:Cumulus Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D066255:EGF Family of Proteins; D047108:Embryonic Development / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000494:pharmacology; D006107:Granulosa Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008024:Ligands; D007986:Luteinizing Hormone / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D020890:Neuregulin-1 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D009865:Oocytes / Q000166:cytology* / Q000187:drug effects; D010060:Ovulation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D013997:Time Factors
C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D006063:Chorionic Gonadotropin; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D012333:RNA, Messenger; D007986:Luteinizing Hormone; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases