title: Multiple pathways mediate luteinizing hormone regulation of cGMP signaling in the mouse ovarian follicle.
abstract: Luteinizing hormone (LH) regulation of the epidermal growth factor (EGF) network is critical for oocyte maturation and the ovulatory process. Recent studies have indicated that C-type natriuretic peptide (CNP) and its receptor natriuretic peptide receptor B (NPR2) play an important role in the control of meiotic arrest. Here, we investigated the involvement of the EGF network in the LH-dependent regulation of the CNP/NPR2 axis and cGMP accumulation. LH/hCG treatment causes a major decrease in both cGMP and the CNP precursor (natriuretic peptide precursor C [Nppc]) mRNA accumulation in vivo and in vitro. However, the cGMP downregulation precedes the decrease in Nppc mRNA by more than 1 h. Amphiregulin, an EGF-like factor, suppresses Nppc mRNA levels in cultured follicles to the same extent as LH, and this effect is completely prevented by the EGF receptor (EGFR) kinase inhibitor AG1478. However, the LH-dependent suppression of Nppc is insensitive to AG1478. Similarly, Nppc suppression by LH occurs in follicles from EGFR null mice. These findings document that EGFR signaling is sufficient to downregulate CNP, but is not necessary for LH action. When cGMP concentration in the follicle is measured, the short-term, but not long-term, LH effects on cGMP are prevented by AG1478, suggesting that ligand availability may be responsible for the late response. Human CG decreases the CNP-dependent cGMP synthesis in wild-type and EGFR knockdown cumulus-oocyte complexes. These findings demonstrate that redundant pathways are involved in the regulation of cGMP. EGFR-dependent events are involved in the short-term regulation of cGMP, whereas the long-term effects may involve regulation of the CNP.
authors.affiliation: College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, People's Republic of China Department of Obstetrics, Gynecology and Reproductive Sciences, Center for Reproductive Sciences, The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco (UCSF) Medical Center, UCSF, San Francisco, California.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Center for Reproductive Sciences, The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco (UCSF) Medical Center, UCSF, San Francisco, California.
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Center for Reproductive Sciences, The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco (UCSF) Medical Center, UCSF, San Francisco, California.
authors.forename: Alberuni Musa
authors.initials: AM
authors.lastname: Zamah
authors.affiliation: College of Animal Science and Technology, Northwest A&F, Yangling, Shaanxi, People's Republic of China caobinyun@126.com.
authors.forename: Binyun
authors.initials: B
authors.lastname: Cao
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Center for Reproductive Sciences, The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco (UCSF) Medical Center, UCSF, San Francisco, California contim@obgyn.ucsf.edu.
authors.forename: Marco
authors.initials: M
authors.lastname: Conti
mesh_terms: D066258:Amphiregulin / Q000494:pharmacology; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007986:Luteinizing Hormone / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D020098:Natriuretic Peptide, C-Type / Q000378:metabolism; D006080:Ovarian Follicle / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D066258:Amphiregulin; D020098:Natriuretic Peptide, C-Type; D007986:Luteinizing Hormone; D066246:ErbB Receptors; D006152:Cyclic GMP
keywords: cyclic-AMP; cyclic-GMP; epidermal growth factor; granulosa cells; luteinizing hormone (LH/LH receptor); natriuretic peptide precursor type C; oocyte maturation; oocyte meiotic arrest; ovary; preovulatory follicle; signal transduction
references.citation: Science. 2010 Oct 15;330(6002):366-9
references.pmid: 20947764
references.citation: Recent Prog Horm Res. 2002;57:195-220
references.pmid: 12017544
references.citation: Acta Physiol Scand. 1990 Jul;139(3):511-7
references.pmid: 2173353
references.citation: Biol Reprod. 2004 Apr;70(4):1178-87
references.pmid: 14681202
references.citation: J Clin Invest. 2004 Jul;114(2):196-205
references.pmid: 15254586
references.citation: Mol Cell Endocrinol. 2002 Feb 22;187(1-2):153-9
references.pmid: 11988323
references.citation: Biol Reprod. 2000 Dec;63(6):1610-6
references.pmid: 11090427
references.citation: Mol Endocrinol. 1992 Feb;6(2):272-8
references.pmid: 1314958
references.citation: Endocrinology. 2013 Sep;154(9):3401-9
references.pmid: 23787120
references.citation: Mol Endocrinol. 2013 Sep;27(9):1483-91
references.pmid: 23836924
references.citation: Reproduction. 2012 Aug;144(2):187-93
references.pmid: 22696190
references.citation: Development. 2008 Jun;135(12):2127-37
references.pmid: 18506027
references.citation: Reproduction. 2005 Dec;130(6):791-9
references.pmid: 16322539
references.citation: Reproduction. 2010 Nov;140(5):655-62
references.pmid: 20826538
references.citation: Endocrinology. 2005 Mar;146(3):1236-44
references.pmid: 15576461
references.citation: Endocrinology. 2005 Jan;146(1):77-84
references.pmid: 15459120
references.citation: Mol Cell Endocrinol. 2012 Jun 5;356(1-2):65-73
references.pmid: 22101318
references.citation: Mol Endocrinol. 2006 Apr;20(4):715-23
references.pmid: 16051667
references.citation: Biol Reprod. 2009 Sep;81(3):595-604
references.pmid: 19474061
references.citation: Genesis. 2009 Feb;47(2):85-92
references.pmid: 19115345
references.citation: Mol Cell Biol. 2007 Mar;27(5):1914-24
references.pmid: 17194751
references.citation: Endocrinology. 2006 May;147(5):2280-6
references.pmid: 16439460
references.citation: Mol Endocrinol. 2001 Feb;15(2):209-18
references.pmid: 11158328
references.citation: Hum Reprod. 2010 Oct;25(10):2569-78
references.pmid: 20719813
references.citation: PLoS One. 2011;6(6):e21574
references.pmid: 21738714
references.citation: Development. 2008 Oct;135(19):3229-38
references.pmid: 18776144
references.citation: Endocrinology. 2002 Jun;143(6):2221-32
references.pmid: 12021186
references.citation: Science. 2004 Jan 30;303(5658):682-4
references.pmid: 14726596
references.citation: Hum Mol Genet. 2013 Jan 15;22(2):345-57
references.pmid: 23065701
references.citation: Endocr Rev. 2002 Apr;23(2):141-74
references.pmid: 11943741
references.citation: J Clin Invest. 2010 Apr;120(4):963-72
references.pmid: 20364094
references.citation: J Biol Chem. 1992 Mar 5;267(7):4479-88
references.pmid: 1311310
references.citation: Mol Endocrinol. 2008 Apr;22(4):924-36
references.pmid: 18187604
references.citation: Mol Endocrinol. 2006 Jun;20(6):1352-65
references.pmid: 16543407
references.citation: Development. 2009 Jun;136(11):1869-78
references.pmid: 19429786
references.citation: Mol Endocrinol. 2012 Jul;26(7):1158-66
references.pmid: 22595960
references.citation: Reprod Biol Endocrinol. 2012 Mar 29;10:25
references.pmid: 22455442
references.citation: Dev Biol. 2012 Jun 15;366(2):308-16
references.pmid: 22546688
references.citation: Biol Reprod. 2001 Jul;65(1):188-96
references.pmid: 11420239
references.citation: Hum Reprod. 2011 Nov;26(11):3094-101
references.pmid: 21865234
references.citation: J Mol Endocrinol. 2004 Aug;33(1):281-91
references.pmid: 15291759