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Participation of Mitogen-Activated Protein Kinase in Luteinizing Hormone-Induced Differential Regulation of Steroidogenesis and Steroidogenic Gene Expression in Mural and Cumulus Granulosa Cells of Mouse Preovulatory Follicles¹

Department of Obstetrics and Gynecology,⁶ Stanford University, Stanford, California 94305 Department of Obstetrics, Gynecology, and Reproductive Sciences,⁷ University of California, San Francisco, California 94143-0132

ABSTRACT

The LH surge induces the terminal differentiation and onset of luteinization in granulosa cells of preovulatory follicles, a process that involves the differential expression of genes essential for steroidogenesis and appears to be mediated by complex signaling pathways. The objective of this study was to investigate whether these processes that commonly occur in mural granulosa cells (MGCs) also occur in cumulus cells, and whether they are mediated by the mitogen-activated protein kinase (MAPK), specifically MAPK3/1 (also commonly known as extracellular signal-regulated kinase 1&2, ERK1/2). The standard superovulation model for premature female mice was used to obtain MGCs and cumulus-oocyte complexes (COCs), and sensitive real-time RT-PCR was used to simultaneously detect the expression levels of transcripts encoding key steroidogenic enzymes in the same sample. We observed significant downregulation of Cyp19a1 and upregulation of Star and Cyp11a1 mRNA expression in both COCs and MGCs after in vivo administration of hCG or in vitro treatment with gonadotropins or 8-Br-cAMP. This differential pattern of steroidogenic gene expression was correlated with the ultimate changes of circulating estradiol (E₂) and progesterone (P₄) levels after administration of hCG. In vitro, when MGCs and COCs were treated with U0126—a specific inhibitor of MAPK3/1 activation—gonadotropin-induced P₄ production, 8-Br-cAMP-induced P₄ production, and expression of Star and Cyp11a1 mRNA were significantly downregulated, whereas the levels of E₂ and Cyp19a1 mRNA in the same samples were significantly upregulated. We conclude that the surge of preovulatory LH induces the differential expression of transcripts encoding key steroidogenic enzymes essential for E₂ and P₄ synthesis in both cumulus and MGCs, and this process is mediated by the MAPK3/1-dependent pathway.

cumulus cells, granulosa cells, luteinizing hormone, MAPK3/1, ovulation, signal transduction, steroidogenesis, steroidogenic gene expression

³Current address: The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609.

⁴Current address: Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10, DK-8000 Aarhus C, Denmark.

⁵Current address: Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100083, China.

¹Supported by National Institute of Child Health and Human Development grant HD31579 to L.C.G. and by fellowships from Diagnostic Systems Laboratories, Inc., to M.N. and M.T.O.

Correspondence: ² Linda C. Giudice, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, 505 Parnassus Ave., M1496, Box 0132, San Francisco, CA 94143-0132. FAX: 415 476 1811; e-mail: giudice{at}obgyn.ucsf.edu