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BOR - Papers in Press, published online ahead of print August 13, 2008.
Biol Reprod 2008, 10.1095/biolreprod.108.069435
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BIOLOGY OF REPRODUCTION 79, 1074–1083 (2008)
DOI: 10.1095/biolreprod.108.069435
© 2008 by the Society for the Study of Reproduction, Inc.

Impaired Follicle Development and Infertility in Female Mice Lacking Steroidogenic Factor 1 in Ovarian Granulosa Cells1

Carla Pelusi 3, Yayoi Ikeda 4, Mohamad Zubair 3, and Keith L. Parker 2 3

Departments of Internal Medicine and Pharmacology,3 University of Texas Southwestern Medical Center, Dallas, Texas 75390-8857 Department of Histology and Cell Biology,4 Yokohama City University School of Medicine, Yokohama 236-0004, Japan

ABSTRACT

The nuclear receptor steroidogenic factor 1 (SF-1 [officially designated NR5A1]) is essential for fetal gonadal development, but its roles in postnatal ovarian function are less well defined. Herein, we have extended our analyses of knockout (KO) mice with markedly decreased SF-1 expression in granulosa cells. As described, these SF-1 KO mice had hypoplastic ovaries that contained a decreased number of follicles and lacked corpora lutea. In the present study, we showed that SF-1 KO mice exhibited abnormal estrous cycles, were infertile, and released significantly fewer oocytes in response to a standard superovulation regimen. Moreover, they had blunted induction of plasma estradiol in response to gonadotropins. The granulosa cell-specific SF-1 KO also significantly affected ovarian expression of putative SF-1 target genes. Consistent with their decreased follicle number, these mice had reduced ovarian expression of anti-müllerian hormone (Amh), which correlates with the reserve pool of ovarian follicles, as well as decreased gonadotropin-induced ovarian expression of aromatase (Cyp19a1) and cyclin D2 (Ccnd2). In contrast, perhaps because of their abnormal cyclicity, SF-1 KO ovaries had higher basal expression of inhibin-alpha. They also had decreased immunoreactivity for genes related to proliferation (Ccnd2 and Mki67 [also known as Ki67]) and increased expression of Cdkn1b, also known as p27, which inhibits cyclin-dependent kinases, arguing for a role of SF-1 in granulosa cell proliferation. These findings demonstrate that SF-1 has a key role in female reproduction via essential actions in granulosa cells.

aromatase, Cre/loxP, estrogen, follicular development, granulosa cells, nuclear receptor, ovary, proliferation, steroidogenic factor 1

FOOTNOTES

1Supported by grant R01 HD046743 from the National Institutes of Health to K.L.P.

Correspondence: 2FAX: 214 648 8917; e-mail: Keith.Parker{at}utsouthwestern.edu






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