Cell-Specific Knockout of Steroidogenic Factor 1 Reveals Its Essential Roles in Gonadal Function

Abstract

Knockout (KO) mice lacking the orphan nuclear receptor steroidogenic factor 1 (SF-1, officially designated Nr5a1) have a compound endocrine phenotype that includes adrenal and gonadal agenesis, impaired expression of pituitary gonadotropins, and structural abnormalities of the ventromedial hypothalamic nucleus. To inactivate a conditional SF-1 allele in the gonads, we targeted the expression of Cre recombinase with a knock-in allele of the anti-Müllerian hormone type 2 receptor locus. In testes, Cre was expressed in Leydig cells. The testes of adult gonad-specific SF-1 KO mice remained at the level of the bladder and were markedly hypoplastic, due at least partly to impaired spermatogenesis. Histological abnormalities of the testes were seen from early developmental stages and were associated with markedly decreased Leydig cell expression of two essential components of testosterone biosynthesis, Cyp11a and the steroidogenic acute regulatory protein. In females, the anti-Müllerian hormone type 2 receptor-Cre allele directed Cre expression to granulosa cells. Although wild-type and SF-1 KO ovaries were indistinguishable during embryogenesis and at birth, adult females were sterile and their ovaries lacked corpora lutea and contained hemorrhagic cysts resembling those in estrogen receptor alpha and aromatase KO mice. Collectively, these studies establish definitively that SF-1 expression in the gonads is essential for normal reproductive development and function.

Aromatase expression in the ovary: Hormonal and molecular regulation

“…Ovaries of granulosa-cell-specific SF-1 knockout mice contain hemorrhagic follicles [120]; similar defects were found in the ovaries of the aromatase knockout mice [19]. Moreover, exogenous expression of SF-1 in rat granulosa cells seems to stimulate aromatase expression.…”

The expression pattern of nuclear receptors during cerebellar development

“…However, in control experiments, they were detected in other tissues in which each was already known to be expressed (Sladek et al, 1990;Zennaro et al, 1997;Zineb et al, 1998;Tulachan et al, 2003;Jeyasuria et al, 2004;Tanaka et al, 2006). These results suggest that they are not expressed or expressed at a very low level in the cerebellum at this stage of development.…”

Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1

“…NATURE COMMUNICATIONS | DOI: 10.1038/ncomms4634 ARTICLE As Ad4BP/SF-1-deficient mice die shortly after birth with dysgenesis of the adrenal gland and gonads, evaluating the postnatal effects of the gene under null conditions was a challenge. To overcome this limitation, pituitary gonadotropeand gonad-specific Ad4BP/SF-1-deficient mice were generated 44,45 . As expected, these mice survived postnatally, although they displayed structurally and functionally impaired tissues.…”