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

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.

Regulation of Steroidogenesis, Development, and Cell Differentiation by Steroidogenic Factor-1 and Liver Receptor Homolog-1

“…These findings suggest that both factors have unique functions. In GCs, it is noteworthy that ovarian estrogen production is reduced by repression of aromatase expression in SF-1 GC-KO mice (Pelusi et al, 2008), but it is unaffected in LRH-1 GC-KO mice (Duggavathi et al, 2008). Further studies are necessary to reveal the functions of SF-1 and LRH-1 in steroidogenesis.…”

“…Consistent with this hypothesis, the testes fail to descend (an androgen-dependent developmental process) and are hypoplastic. In GC-specific KO mice, there are numerous ovarian defects (Pelusi et al, 2008). In these mice, the ovaries are hypoplastic, adults are sterile, and ovaries show reduced numbers of oocytes.…”

“…It is well known that SF-1 and LRH-1 are involved in the transcription of steroidogenesis-related genes Lee and Moore, 2008;Parker and Schimmer, 1997;Schimmer and White, 2010;Wang et al, 2001;Yazawa et al, 2014;Yazawa et al, 2011) and that steroidogenesis is markedly influenced by a deficiency of either factor (Duggavathi et al, 2008;Jeyasuria et al, 2004;Pelusi et al, 2008;Zhang et al, 2013). SF-1 is also known to be involved in the development of steroidogenic organs Parker and Schimmer, 1997) and the differentiation of steroidogenic cells Yazawa et al, 2009;Yazawa et al, 2006).…”

NR5A1 is required for functional maturation of Sertoli cells during postnatal development

“…The gonad-specific Nr5a1 KO mice survive adulthood, and previous studies have demonstrated that the testes and ovaries are affected (Jeyasuria et al 2004, Pelusi et al 2008. In the previous study on the gonad-specific Nr5a1 KO testes, no Leydig cells were detected in the interstitium but Sertoli cells were detected within the testicular cord during embryonic development (Jeyasuria et al 2004).…”

NR5A1 (nuclear receptor subfamily 5, group A, member 1)

“…Studies of both complete and tissue-specific knockout mice have demonstrated that SF-1 is a key factor for the development of the adrenal glands, gonads, ventromedial hypothalamus and in pituitary gonadotropes functions Sadovsky et al, 1995;Shinoda et al, 1995;Ikeda et al, 1995;Zhao et al, 2001). To characterize the role of SF-1 in different tissues and to distinguish between the direct and secondary effects of SF-1 deficiency, Keith Parker's laboratory developed mice models that are specifically deleted for Sf-1 in gonadotrope cells, gonads and VMH by using the Cre/lox approach (Jeyasuria et al, 2004;Pelusi et al, 2008;Zhao et al, 2008). Role in adrenal and gonads Sf-1 null mice lack adrenal glands and gonads and die from adrenal insufficiency within the first week after birth.…”