Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 324 (5929): 938-941

Copyright © 2009 by the American Association for the Advancement of Science

MAPK3/1 (ERK1/2) in Ovarian Granulosa Cells Are Essential for Female Fertility

Heng-Yu Fan,1 Zhilin Liu,1 Masayuki Shimada,2 Esta Sterneck,3 Peter F. Johnson,4 Stephen M. Hedrick,5 JoAnne S. Richards1,*

Abstract: A surge of luteinizing hormone (LH) from the pituitary gland triggers ovulation, oocyte maturation, and luteinization for successful reproduction in mammals. Because the signaling molecules RAS and ERK1/2 (extracellular signal–regulated kinases 1 and 2) are activated by an LH surge in granulosa cells of preovulatory follicles, we disrupted Erk1/2 in mouse granulosa cells and provide in vivo evidence that these kinases are necessary for LH-induced oocyte resumption of meiosis, ovulation, and luteinization. In addition, biochemical analyses and selected disruption of the Cebpb gene in granulosa cells demonstrate that C/EBPβ (CCAAT/Enhancer-binding protein–β) is a critical downstream mediator of ERK1/2 activation. Thus, ERK1/2 and C/EBPβ constitute an in vivo LH-regulated signaling pathway that controls ovulation- and luteinization-related events.

1 Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
2 Department of Applied Animal Science, Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima, 739-8528, Japan.
3 Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute–Frederick, Frederick, MD 21702–1201, USA.
4 Basic Research Laboratory, Center for Cancer Research, National Cancer Institute–Frederick, Frederick, MD 21702–1201, USA.
5 Molecular Biology Section, Division of Biological, Sciences and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

* To whom correspondence should be addressed. E-mail: joanner{at}

Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice.
H. Wang, M. Larson, A. Jablonka-Shariff, C. A. Pearl, W. L. Miller, P. M. Conn, I. Boime, and T. R. Kumar (2014)
PNAS 111, 5735-5740
   Abstract »    Full Text »    PDF »
Effect of Epidermal Growth Factor-Like Peptides on the Metabolism of In Vitro- Matured Mouse Oocytes and Cumulus Cells.
D. Richani, M. L. Sutton-McDowall, L. A. Frank, R. B. Gilchrist, and J. G. Thompson (2014)
Biol Reprod 90, 49
   Abstract »    Full Text »    PDF »
Treatment With Anticancer Agents Induces Dysregulation of Specific Wnt Signaling Pathways in Human Ovarian Luteinized Granulosa Cells In Vitro.
A. M. Sanchez, V. Giorgione, P. Vigano, E. Papaleo, M. Candiani, G. Mangili, and P. Panina-Bordignon (2013)
Toxicol. Sci. 136, 183-192
   Abstract »    Full Text »    PDF »
Ovarian signalling pathways regulated by leptin during the ovulatory process.
M. P. Di Yorio, M. G. Bilbao, A. M. Biagini-Majorel, and A. G. Faletti (2013)
Reproduction 146, 647-658
   Abstract »    Full Text »    PDF »
Oocyte Maturation and Fertilization in Marine Nemertean Worms: Using Similar Sorts of Signaling Pathways as in Mammals, but Often With Differing Results.
S. A. Stricker, C. Cline, and D. Goodrich (2013)
Biol. Bull. 224, 137-155
   Abstract »    Full Text »    PDF »
Mode of oocyte maturation affects EGF-like peptide function and oocyte competence.
D. Richani, L. J. Ritter, J. G. Thompson, and R. B. Gilchrist (2013)
Mol. Hum. Reprod. 19, 500-509
   Abstract »    Full Text »    PDF »
Calcium influx in mammalian eggs.
C. Wang and Z. Machaty (2013)
Reproduction 145, R97-R105
   Abstract »    Full Text »    PDF »
Inhibition of MAP2K and GSK3 Signaling Promotes Bovine Blastocyst Development and Epiblast-Associated Expression of Pluripotency Factors.
D. Harris, B. Huang, and B. Oback (2013)
Biol Reprod 88, 74
   Abstract »    Full Text »    PDF »
Signaling pathways regulating FSH- and amphiregulin-induced meiotic resumption and cumulus cell expansion in the pig.
R. Prochazka, M. Blaha, and L. Nemcova (2012)
Reproduction 144, 535-546
   Abstract »    Full Text »    PDF »
Generation of Mice Expressing Only the Long Form of the Prolactin Receptor Reveals That Both Isoforms of the Receptor Are Required for Normal Ovarian Function.
J. A. Le, H. M. Wilson, A. Shehu, J. Mao, Y. S. Devi, J. Halperin, T. Aguilar, A. Seibold, E. Maizels, and G. Gibori (2012)
Biol Reprod 86, 86
   Abstract »    Full Text »    PDF »
Reproductive Tissues Maintain Insulin Sensitivity in Diet-Induced Obesity.
S. Wu, S. Divall, F. Wondisford, and A. Wolfe (2012)
Diabetes 61, 114-123
   Abstract »    Full Text »    PDF »
New insights into the role of centrosomes in mammalian fertilization and implications for ART.
H. Schatten and Q.-Y. Sun (2011)
Reproduction 142, 793-801
   Abstract »    Full Text »    PDF »
Differences in the participation of TGFB superfamily signalling pathways mediating porcine and murine cumulus cell expansion.
R. B. Gilchrist and L. J. Ritter (2011)
Reproduction 142, 647-657
   Abstract »    Full Text »    PDF »
Positive Feedback Loop Between Prostaglandin E2 and EGF-Like Factors Is Essential for Sustainable Activation of MAPK3/1 in Cumulus Cells During In Vitro Maturation of Porcine Cumulus Oocyte Complexes.
Y. Yamashita, M. Okamoto, I. Kawashima, T. Okazaki, R. Nishimura, Y. Gunji, M. Hishinuma, and M. Shimada (2011)
Biol Reprod 85, 1073-1082
   Abstract »    Full Text »    PDF »
Expression and regulation of sFRP family members in human granulosa cells.
E. Maman, Y. Yung, B. Cohen, S. Konopnicki, M. Dal Canto, R. Fadini, H. Kanety, A. Kedem, J. Dor, and A. Hourvitz (2011)
Mol. Hum. Reprod. 17, 399-404
   Abstract »    Full Text »    PDF »
Effect of epidermal growth factor-like peptides on pig cumulus cell expansion, oocyte maturation, and acquisition of developmental competence in vitro: comparison with gonadotropins.
R. Prochazka, M. Petlach, E. Nagyova, and L. Nemcova (2011)
Reproduction 141, 425-435
   Abstract »    Full Text »    PDF »
Inhibition of MAPK by Prolactin Signaling through the Short Form of Its Receptor in the Ovary and Decidua: INVOLVEMENT OF A NOVEL PHOSPHATASE.
Y. S. Devi, A. M. Seibold, A. Shehu, E. Maizels, J. Halperin, J. Le, N. Binart, L. Bao, and G. Gibori (2011)
J. Biol. Chem. 286, 7609-7618
   Abstract »    Full Text »    PDF »
Reactive oxygen species are indispensable in ovulation.
K. Shkolnik, A. Tadmor, S. Ben-Dor, N. Nevo, D. Galiani, and N. Dekel (2011)
PNAS 108, 1462-1467
   Abstract »    Full Text »    PDF »
Simulated physiological oocyte maturation (SPOM): a novel in vitro maturation system that substantially improves embryo yield and pregnancy outcomes.
F. K. Albuz, M. Sasseville, M. Lane, D. T. Armstrong, J. G. Thompson, and R. B. Gilchrist (2010)
Hum. Reprod. 25, 2999-3011
   Abstract »    Full Text »    PDF »
Human oocyte maturation is dependent on LH-stimulated accumulation of the epidermal growth factor-like growth factor, amphiregulin.
A. M. Zamah, M. Hsieh, J. Chen, J. L. Vigne, M. P. Rosen, M. I. Cedars, and M. Conti (2010)
Hum. Reprod. 25, 2569-2578
   Abstract »    Full Text »    PDF »
Growth differentiation factor 9 signaling requires ERK1/2 activity in mouse granulosa and cumulus cells.
M. Sasseville, L. J. Ritter, T. M. Nguyen, F. Liu, D. G. Mottershead, D. L. Russell, and R. B. Gilchrist (2010)
J. Cell Sci. 123, 3166-3176
   Abstract »    Full Text »    PDF »
Prophase I arrest and progression to metaphase I in mouse oocytes: comparison of resumption of meiosis and recovery from G2-arrest in somatic cells.
P. Solc, R. M. Schultz, and J. Motlik (2010)
Mol. Hum. Reprod. 16, 654-664
   Abstract »    Full Text »    PDF »
The Rhox genes.
J. A. MacLean II and M. F. Wilkinson (2010)
Reproduction 140, 195-213
   Abstract »    Full Text »    PDF »
Molecular Symbiosis of CHOP and C/EBP{beta} Isoform LIP Contributes to Endoplasmic Reticulum Stress-Induced Apoptosis.
C.-B. Chiribau, F. Gaccioli, C. C. Huang, C. L. Yuan, and M. Hatzoglou (2010)
Mol. Cell. Biol. 30, 3722-3731
   Abstract »    Full Text »    PDF »
RSK-Mediated Phosphorylation in the C/EBP{beta} Leucine Zipper Regulates DNA Binding, Dimerization, and Growth Arrest Activity.
S. Lee, J. D. Shuman, T. Guszczynski, K. Sakchaisri, T. Sebastian, T. D. Copeland, M. Miller, M. S. Cohen, J. Taunton, R. C. Smart, et al. (2010)
Mol. Cell. Biol. 30, 2621-2635
   Abstract »    Full Text »    PDF »
Impact of linoleic acid on bovine oocyte maturation and embryo development.
W. F. Marei, D. C. Wathes, and A. A. Fouladi-Nashta (2010)
Reproduction 139, 979-988
   Abstract »    Full Text »    PDF »
Lack of Functional Pregnancy-Associated Plasma Protein-A (PAPPA) Compromises Mouse Ovarian Steroidogenesis and Female Fertility.
M. Nyegaard, M. T. Overgaard, Y. Q. Su, A. E. Hamilton, J. Kwintkiewicz, M. Hsieh, N. R. Nayak, M. Conti, C. A. Conover, and L. C. Giudice (2010)
Biol Reprod 82, 1129-1138
   Abstract »    Full Text »    PDF »
The differential transcriptome and ontology profiles of floating and cumulus granulosa cells in stimulated human antral follicles.
S. Koks, A. Velthut, A. Sarapik, S. Altmae, E. Reinmaa, L.C. Schalkwyk, C. Fernandes, H.V. Lad, U. Soomets, U. Jaakma, et al. (2010)
Mol. Hum. Reprod. 16, 229-240
   Abstract »    Full Text »    PDF »
Crosstalk between C/EBP{beta} phosphorylation, arginine methylation, and SWI/SNF/Mediator implies an indexing transcription factor code.
E. Kowenz-Leutz, O. Pless, G. Dittmar, M. Knoblich, and A. Leutz (2010)
EMBO J. 29, 1105-1115
   Abstract »    Full Text »    PDF »
Progesterone Receptor-Induced Gene Expression in Primary Mouse Granulosa Cell Cultures.
V. Sriraman, M. Sinha, and J. S. Richards (2010)
Biol Reprod 82, 402-412
   Abstract »    Full Text »    PDF »
Paracrine support of ovarian stimulation.
S. G. Hillier (2009)
Mol. Hum. Reprod. 15, 843-850
   Abstract »    Full Text »    PDF »
The Effect of Linolenic Acid on Bovine Oocyte Maturation and Development.
W. F. Marei, D. C. Wathes, and A. A. Fouladi-Nashta (2009)
Biol Reprod 81, 1064-1072
   Abstract »    Full Text »    PDF »
Regulation and action of fibroblast growth factor 17 in bovine follicles.
M F Machado, V M Portela, C A Price, I B Costa, P Ripamonte, R L Amorim, and J Buratini Jr (2009)
J. Endocrinol. 202, 347-353
   Abstract »    Full Text »    PDF »
Cell Type-Specific Targeted Mutations of Kras and Pten Document Proliferation Arrest in Granulosa Cells versus Oncogenic Insult to Ovarian Surface Epithelial Cells.
H.-Y. Fan, Z. Liu, M. Paquet, J. Wang, J. P. Lydon, F. J. DeMayo, and J. S. Richards (2009)
Cancer Res. 69, 6463-6472
   Abstract »    Full Text »    PDF »
Ovulation Signals.
R. Duggavathi and B. D. Murphy (2009)
Science 324, 890-891
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882