title: Epidermal growth factor receptor kinase activity is required for gap junction closure and for part of the decrease in ovarian follicle cGMP in response to LH.
abstract: The meiotic cell cycle in mouse oocytes is arrested in prophase, and then restarted when LH acts on the surrounding granulosa cells. The granulosa cells keep meiosis arrested by providing a source of cGMP that diffuses into the oocyte through gap junctions, and LH restarts the cell cycle by closing the junctions and by decreasing granulosa cell cGMP, thus lowering oocyte cGMP. Epidermal growth factor receptor (EGFR) activation is an essential step in triggering LH-induced meiotic resumption, but its relationship to the cGMP decrease in the follicle is incompletely understood, and its possible function in causing gap junction closure has not been investigated. Here, we use EGFR agonists (epiregulin and amphiregulin) and an EGFR kinase inhibitor (AG1478) to study the function of the EGFR in the signaling pathways leading to the release of oocytes from prophase arrest. Our results indicate that the EGFR kinase contributes to LH-induced meiotic resumption in two different ways. First, it is required for gap junction closure. Second, it is required for an essential component of the decrease in follicle cGMP. Our data show that the EGFR kinase-dependent component of the cGMP decrease is required for LH-induced meiotic resumption, but they also indicate that an as yet unidentified pathway accounts for a large part of the cGMP decrease.
authors.affiliation: Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut 06032, USA.
authors.forename: Rachael P
authors.initials: RP
authors.lastname: Norris
authors.forename: Marina
authors.initials: M
authors.lastname: Freudzon
authors.forename: Viacheslav O
authors.initials: VO
authors.lastname: Nikolaev
authors.forename: Laurinda A
authors.initials: LA
authors.lastname: Jaffe
mesh_terms: D066258:Amphiregulin; D000818:Animals; D006152:Cyclic GMP / Q000502:physiology*; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066260:Epiregulin; D066246:ErbB Receptors / Q000502:physiology*; D005260:Female; D017629:Gap Junctions / Q000502:physiology*; D006023:Glycoproteins / Q000494:pharmacology; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000502:physiology*; D008540:Meiosis / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D006080:Ovarian Follicle / Q000502:physiology*; D011799:Quinazolines; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D066260:Epiregulin; C587881:Ereg protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D004815:Epidermal Growth Factor; D007986:Luteinizing Hormone; D066246:ErbB Receptors; D006152:Cyclic GMP
references.citation: Endocrinology. 2005 Jan;146(1):77-84
references.pmid: 15459120
references.citation: Hum Reprod. 1991 Mar;6(3):411-22
references.pmid: 1659586
references.citation: Dev Biol. 2003 Nov 1;263(1):126-38
references.pmid: 14568551
references.citation: Development. 2008 Oct;135(19):3229-38
references.pmid: 18776144
references.citation: Mol Endocrinol. 2010 Mar;24(3):552-60
references.pmid: 20093417
references.citation: J Exp Med. 1935 Oct 31;62(5):665-75
references.pmid: 19870440
references.citation: Endocrinology. 2005 Mar;146(3):1236-44
references.pmid: 15576461
references.citation: Biol Reprod. 2009 Sep;81(3):595-604
references.pmid: 19474061
references.citation: Dev Biol. 1986 Dec;118(2):343-51
references.pmid: 3025032
references.citation: Mol Cell Biol. 2007 Mar;27(5):1914-24
references.pmid: 17194751
references.citation: Reproduction. 2004 Aug;128(2):153-62
references.pmid: 15280554
references.citation: Endocrinology. 2006 May;147(5):2280-6
references.pmid: 16439460
references.citation: Endocrinology. 1985 Jan;116(1):406-9
references.pmid: 2578036
references.citation: Biochem J. 1986 Sep 1;238(2):597-604
references.pmid: 3026357
references.citation: Development. 2010 Apr;137(8):1297-304
references.pmid: 20223764
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 21;102(25):8922-6
references.pmid: 15956199
references.citation: J Exp Zool. 1988 Jan;245(1):86-96
references.pmid: 2832512
references.citation: Science. 2004 Dec 10;306(5703):1947-50
references.pmid: 15591206
references.citation: Science. 2004 Jan 30;303(5658):682-4
references.pmid: 14726596
references.citation: Mol Endocrinol. 2008 Apr;22(4):924-36
references.pmid: 18187604
references.citation: Dev Biol. 2005 Dec 15;288(2):397-404
references.pmid: 16289135
references.citation: J Cell Biol. 2010 Jan 25;188(2):199-207
references.pmid: 20083600
references.citation: Development. 2009 Jun;136(11):1869-78
references.pmid: 19429786
references.citation: Mol Endocrinol. 2010 Jun;24(6):1230-9
references.pmid: 20382892
references.citation: Endocrinology. 2008 Nov;149(11):5549-56
references.pmid: 18653716
references.citation: Dev Biol. 2005 Nov 15;287(2):249-61
references.pmid: 16229830
references.citation: Science. 1995 Mar 24;267(5205):1782-8
references.pmid: 7892601