Document Detail


LH-induced neuregulin 1 (NRG1) type III transcripts control granulosa cell differentiation and oocyte maturation.
MedLine Citation:
PMID:  21047912     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Noritaka Noma; Ikko Kawashima; Heng-Yu Fan; Youko Fujita; Tomoko Kawai; Yoshinori Tomoda; Toshihiro Mihara; Joanne S Richards; Masayuki Shimada
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-11-03
Journal Detail:
Title:  Molecular endocrinology (Baltimore, Md.)     Volume:  25     ISSN:  1944-9917     ISO Abbreviation:  Mol. Endocrinol.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-01-03     Completed Date:  2011-04-11     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  8801431     Medline TA:  Mol Endocrinol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  104-16     Citation Subset:  IM    
Affiliation:
Laboratory of Reproductive Endocrinology, Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan.
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MeSH Terms
Descriptor/Qualifier:
Animals
Base Sequence
Cell Differentiation / drug effects*
Cells, Cultured
Chorionic Gonadotropin / pharmacology
Cumulus Cells / cytology,  drug effects,  enzymology
Embryonic Development / drug effects
Enzyme Activation / drug effects
Extracellular Signal-Regulated MAP Kinases / metabolism
Female
Gene Expression Regulation / drug effects
Glycoproteins / pharmacology
Granulosa Cells / cytology*,  drug effects,  enzymology
Humans
Intercellular Signaling Peptides and Proteins / pharmacology
Ligands
Luteinizing Hormone / pharmacology*
Mice
Molecular Sequence Data
Neuregulin-1 / genetics*,  metabolism,  pharmacology
Oocytes / cytology*,  drug effects
Ovulation / drug effects
Promoter Regions, Genetic / genetics
Proto-Oncogene Proteins c-akt / metabolism
RNA, Messenger / genetics,  metabolism
Receptor Protein-Tyrosine Kinases / metabolism
Time Factors
Grant Support
ID/Acronym/Agency:
HD-07495/HD/NICHD NIH HHS; HD-16229/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Chorionic Gonadotropin; 0/Glycoproteins; 0/Intercellular Signaling Peptides and Proteins; 0/Ligands; 0/Neuregulin-1; 0/Nrg1 protein, mouse; 0/RNA, Messenger; 117147-70-3/amphiregulin; 9002-67-9/Luteinizing Hormone; EC 2.7.10.1/Receptor Protein-Tyrosine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases
Comments/Corrections

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