Steroidogenic factor 1 (SF-1), an orphan nuclear receptor, initially was isolated as a key regulator of the tissue-specific expression of the cytochrome P450 steroid hydroxylases. Thereafter, analyses of sites of SF-1 expression during mouse embryological development hinted at considerably expanded roles for SF-1, roles that were strikingly confirmed through the analyses of SF-1 knockout mice. These SF-1 knockout mice exhibited adrenal and gonadal agenesis, associated with male-to-female sex reversal of their internal and external genitalia and death from adrenocortical insufficiency. These findings showed unequivocally that SF-1 is essential for the embryonic survival of the primary steroidogenic organs. SF-1 knockout mice also had impaired pituitary expression of gonadotropins and agenesis of the ventromedial hypothalamic nucleus (VMH), establishing that SF-1 regulates reproductive function at all three levels of the hypothalamic-pituitary gonadal axis. This article reviews the experiments that have defined these essential roles of SF-1 in endocrine development and highlights important areas for future studies.
"For example, steroidogenic factor 1 (SF-1/Nr5a1) encodes an orphan nuclear receptor that plays an essential role in the development and function of pituitary gonadotropes , adrenal glands, gonads, and ventromedial hypothalamus (Ingraham et al., 1994; Luo et al., 1999; Zhao et al., 2001). Homozygous SF-1/Nr5a1 knockout mice display systemic defects in the adrenal glands, gonads, VMH, and decreased expression of the gonadotropin genes and die by postnatal day 8 because of adrenal insufficiency (Ingraham et al., 1994; Luo et al., 1999). Similarly, the histone demethylase Lsd1 is required for proper pituitary development , although Lsd1 2/2 embryos cannot be used for this anlaysis due to early embryonic death (Wang et al., 2007). "
[Show abstract][Hide abstract] ABSTRACT: Tissue-specific expression of the Cre recombinase is a well-established genetic tool to analyze gene function in specific tissues and cell types. In this report, we describe the generation of a new transgenic line that expresses Cre under the control of the rat growth hormone releasing hormone receptor (rGhrhr) promoter. This promoter, chosen to target the anterior pituitary, drives cre-mediated recombination in cells of the Pit1 lineage, including somatotrophs, lactotrophs, and thyrotrophs. Cre activity is first detected at embryonic day 13.5, and gradually increases to reach high level expression by postnatal day 2. In addition to the pituitary, rGhrhr-cre expression was detected in vibrissae and in hair follicles of the proximal limb, but not in other tissues. The rGhrhr-cre line will be a valuable tool for the study of the development of the pituitary Pit1 lineage and for the study of tumorigenesis involving these cells.
"In studies using transgenic mice to define the regions of the hCYP19 gene involved in ovaryspecific expression, we observed that as little as 278 bp of DNA flanking the 5′-end of ovaryspecific hCYP19 exon IIa was sufficient to target ovary-specific expression . This region is highly conserved in the CYP19 genes of rodents and humans and contains cis-acting elements crucial for cAMP induction of hCYP19 promoter activity of human and rat CYP19 genes, including a cAMP response element (CRE)-like sequence (CLS), which binds the CRE-binding protein (CREB) transcription factor  , a binding site for GATA-4  , and a putative nuclear receptor response element that was suggested to bind the orphan nuclear receptor steroidogenic factor 1 (SF-1/NR5A1)  , which is essential for development of the ovaries, testes, adrenals and ventromedial nucleus of the hypothalamus in mice  and plays an important role in the regulation of various members of the cytochrome P450 family of steroid hydroxylases. Within the ovary, SF-1 mRNA and protein are expressed in the granulosa and theca cells of the follicle, the interstitial region and in cells of the corpus luteum. "
[Show abstract][Hide abstract] ABSTRACT: During human gestation, the placental syncytiotrophoblast develops the capacity to synthesize large amounts of estrogen from C(19)-steroids secreted by the fetal adrenals. The conversion of C(19)-steroids to estrogens is catalyzed by aromatase P450 (P450arom), product of the CYP19 gene. The placenta-specific promoter of the hCYP19 gene lies approximately 100,000 bp upstream of the translation initiation site in exon II. In studies using transgenic mice and transfected human trophoblast cells we have defined a 246-bp region upstream of placenta-specific exon I.1 that mediates placental cell-specific expression. Using transgenic mice, we also observed that as little as 278 bp of DNA flanking the 5'-end of ovary-specific hCYP19 exon IIa was sufficient to target ovary-specific expression. This ovary-specific promoter contains response elements that bind cAMP-response element-binding protein (CREB) and the orphan nuclear receptors SF-1 and LRH-1, which are required for cAMP-mediated stimulation of CYP19 expression in granulosa and luteal cells during the estrous cycle and pregnancy. In this article, we review our studies to define genomic regions and response elements that mediate placenta-specific expression of the hCYP19 gene. The temporal and spatial expression of LRH-1 versus SF-1 in the developing gonad during mouse embryogenesis and in the postnatal ovary also will be considered.
The Journal of Steroid Biochemistry and Molecular Biology 08/2007; 106(1-5):62-70. DOI:10.1016/j.jsbmb.2007.05.001 · 3.63 Impact Factor
"The production of specific hormones in the individual cell types of the anterior pituitary gland is under the control of several transcription factors (Lefevre et al. 1987, Nelson et al. 1988, Gage et al. 1996, Hermesz et al. 1996, Poulin et al. 1997, Tremblay et al. 1998, Lanctot et al. 1999, Luo et al. 1999, Kawabe et al. 1999). Pit-1 is known to be a key factor in functional differentiation, promoting the production of GH, PRL and TSH in mice, rats and humans (Mangalam et al. 1989, Ingraham et al. 1990, Simmons et al. 1990). "
[Show abstract][Hide abstract] ABSTRACT: The pituitary-specific POU-homeodomain transcription factor, Pit-1, is known to regulate the expression of the GH gene in somatotropes, prolactin (PRL) in lactotropes, and TSH in thyrotropes. It is not normally expressed in corticotropes or gonadotropes. We addressed the question of whether exogenous Pit-1 was sufficient to induce ectopic transcription of the GH gene in the corticotropic cell line, AtT-20, or the gonadotropic cell line, alpha T3-1. A fusion gene composed of enhanced green fluorescent protein gene and human Pit-1 cDNA was transfected into AtT-20 and alpha T3-1 cells. The endogenous mouse GH mRNA was induced in three of nine AtT-20 cell lines and one of three alpha T3-1 cell lines containing the fusion gene. A small amount of GH protein was also detected in these cell lines. These data indicate that transfected Pit-1 is capable of inducing transcription of the GH gene in AtT-20 cells and alpha T3-1 cells. These data also suggest that synergistic co-factors might be required to transcribe the GH gene effectively for translation into GH protein. Furthermore, our findings support the hypothesis that the function of anterior pituitary cells is determined by the combinatorial action of specific transcription factors.
Journal of Endocrinology 04/2002; 172(3):477-87. · 3.72 Impact Factor
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