SF-1: a critical mediator of steroidogenesis

doi:10.1016/S0303-7207(00)00384-1

Molecular and Cellular Endocrinology

Volume 171, Issues 1–2, 22 January 2001, Pages 5-7

https://doi.org/10.1016/S0303-7207(00)00384-1 Get rights and content

Abstract

Studies in knockout mice have established that the orphan nuclear receptor steroidogenic factor 1 (SF-1) plays essential roles in the development and function of the primary steroidogenic organs. These SF-1 knockout mice lacked adrenal glands and gonads, causing adrenocortical insufficiency and sex reversal of their internal and external genitalia. They also had impaired expression of pituitary gonadotropins and agenesis of the ventromedial hypothalamic nucleus (VMH), confirming roles of SF-1 at all three levels of the hypothalamic–pituitary–steroidogenic organ axis. Ongoing experiments are directed at developing methods to inactivate SF-1 in a tissue-specific manner.

Introduction

Steroidogenic factor 1 (SF-1, officially designated NR5A1) was first identified as an important regulator of the expression of the cytochrome P450 steroid hydroxylases in adrenocortical and gonadal cell lines. After two laboratories independently cloned the SF-1 cDNA (Lala et al., 1992, Honda et al., 1993), DNA sequencing revealed that SF-1 belongs to the nuclear hormone receptor family, zinc-finger transcription factors that mediate transcriptional regulation by steroid hormones, as well as other hydrophobic compounds such as thyroid hormone, vitamin D, and retinoid acid. Many laboratories subsequently showed that SF-1 acts at multiple levels of the hypothalamic-pituitary-steroidogenic organ axis to regulate gene expression of many components that are required for steroidogenesis.

Analyses of SF-1 knockout mice confirmed essential roles of SF-1 in steroidogenesis (reviewed in Parker and Schimmer (1997), Morohashi and Omura (1996), and Sadovsky and Crawford (1998)). Although the very earliest stages of adrenal and gonadal development proceeded in the absence of SF-1, newborn SF-1 knockout mice completely lacked adrenal glands and gonads (Fig. 1). Moreover, because their gonads regressed before sexual differentiation normally occurs, the internal and external urogenital tracts of SF-1 knockout mice developed along the female pathway irrespective of genetic sex.

SF-1 knockout mice also had impaired gonadotrope expression of a number of genes that regulate gonadal steroidogenesis, including luteinizing hormone, follicle-stimulating hormone, and the receptor for gonadotropin-releasing hormone. They further lacked the ventromedial hypothalamic nucleus, a hypothalamic region linked to feeding and appetite regulation and female reproductive behavior. Finally, although the functional consequences remain undefined, the SF-1 knockout mice exhibited defects in their splenic parenchyma (Morohashi et al., 1999).

Section snippets

SF-1's expression profile in human embryos suggests important roles in human development

The human gene encoding SF-1, located on chromosome 9q33, shares extensive homology with its mouse counterpart, suggesting that SF-1 functions in humans much as it does in mice. To explore this model further, we analyzed the spatio-temporal expression pattern of SF-1 in carefully staged sections of human embryos (Hanley et al., 1999).

At 32 days post-ovulation (dpo, A), when the gonadal ridge in human embryos becomes morphologically distinct, SF-1 already was expressed in a cluster of cells

Acknowledgements

We thank Dr Yelena Krimkevich for excellent technical assistance. The studies described here were supported by NIH grant DK54480 (KLP). NAH is a Wellcome Trust Clinical Training Fellow.

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SF-1: a critical mediator of steroidogenesis

Abstract

Introduction

Section snippets

SF-1's expression profile in human embryos suggests important roles in human development

Acknowledgements

Mech. Dev.

J. Biol. Chem.

Cell

Blood