Impaired follicle development and infertility in female mice lacking steroidogenic factor 1 in ovarian granulosa cells.
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.
Pelusi
Carla
C
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8857, USA.
Ikeda
Yayoi
Y
Zubair
Mohamad
M
Parker
Keith L
KL
D000483:Alleles; D000818:Animals; D002452:Cell Count; D030762:Estrous Cycle / Q000235:genetics / Q000502:physiology; D005260:Female; D005298:Fertility / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006107:Granulosa Cells / Q000502:physiology*; D007150:Immunohistochemistry; D007247:Infertility, Female / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size / Q000502:physiology; D006080:Ovarian Follicle / Q000502:physiology*; D010053:Ovary / Q000166:cytology*; D011247:Pregnancy; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054339:Steroidogenic Factor 1 / Q000235:genetics* / Q000502:physiology*; D013480:Superovulation / Q000502:physiology; D014599:Uterus / Q000033:anatomy & histology / Q000254:growth & development
D054339:Steroidogenic Factor 1; D012313:RNA