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Molecular and Cellular Biology, March 2007, p. 1914-1924, Vol. 27, No. 5
0270-7306/07/$08.00+0     doi:10.1128/MCB.01919-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Luteinizing Hormone-Dependent Activation of the Epidermal Growth Factor Network Is Essential for Ovulation{triangledown}

Minnie Hsieh,1 Daekee Lee,2,{ddagger} Sara Panigone,1,{dagger} Kathleen Horner,1 Ruby Chen,1 Alekos Theologis,1 David C. Lee,3,§ David W. Threadgill,2 and Marco Conti1*

Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California 94305,1 Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599,2 Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 275993

Received 10 October 2006/ Returned for modification 1 November 2006/ Accepted 14 December 2006

In the preovulatory ovarian follicle, mammalian oocytes are maintained in prophase meiotic arrest until the luteinizing hormone (LH) surge induces reentry into the first meiotic division. Dramatic changes in the somatic cells surrounding the oocytes and in the follicular wall are also induced by LH and are necessary for ovulation. Here, we provide genetic evidence that LH-dependent transactivation of the epidermal growth factor receptor (EGFR) is indispensable for oocyte reentry into the meiotic cell cycle, for the synthesis of the extracellular matrix surrounding the oocyte that causes cumulus expansion, and for follicle rupture in vivo. Mice deficient in either amphiregulin or epiregulin, two EGFR ligands, display delayed or reduced oocyte maturation and cumulus expansion. In compound-mutant mice in which loss of one EGFR ligand is associated with decreased signaling from a hypomorphic allele of the EGFR, LH no longer signals oocyte meiotic resumption. Moreover, induction of genes involved in cumulus expansion and follicle rupture is compromised in these mice, resulting in impaired ovulation. Thus, these studies demonstrate that LH induction of epidermal growth factor-like growth factors and EGFR transactivation are essential for the regulation of a critical physiological process such as ovulation and provide new strategies for manipulation of fertility.

* Corresponding author. Mailing address: Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5317. Phone: (650) 725-2452. Fax: (650) 725-7102. E-mail: marco.conti{at}stanford.edu.

{triangledown} Published ahead of print on 28 December 2006.

{ddagger} Present address: Division of Molecular Life Sciences, Ewha Womans University, Seoul 120-720, South Korea.

{dagger} Present address: Laboratory of Endocrinological Research, Istituto Auxologico Italiano (IRCCS), Via Zucchi 18, Cusano Milanino (MI) 20095, Italy.

§ Present address: The Office of the Vice President for Research, University of Georgia, Athens, GA 30602.

Molecular and Cellular Biology, March 2007, p. 1914-1924, Vol. 27, No. 5
0270-7306/07/$08.00+0     doi:10.1128/MCB.01919-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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