The nuclear receptor SF-1 (steroidogenic factor-1) is no longer an orphan.

Abstract

The nuclear hormone receptor SF-1 (steroidogenic factor-1, also termed adrenal 4-binding protein or Ad4BP) is a major regulator of the development and function of the hypothalamic‐pituitary‐adrenal and ‐gonadal axes. It was initially discovered as a key transcription factor regulating the cytochrome P450 steroid hydroxylases in the gonads and the adrenal cortex (1, 2). The promoter of the genes regulated by SF-1 contains an AGGTCA-derived motif that binds SF-1. This nuclear receptor also regulates the expression of the steroidogenic acute regulatory protein, the adrenocorticotrophin receptor, and, in the pituitary, the a-subunit of glycoproteins (3). Interestingly, SF-1 seems to play a role in cAMP regulation of transcription in the adrenal cortex. In keeping with a major role for this nuclear receptor in a limited set of organs, SF-1 expression is regulated in a tissue-specific manner. It was initially reported to occur in the adrenocortical cells, ovarian theca and granulosa cells and in the testicular Leydig cells. Later, expression of SF-1 was also found in the ventromedial hypothalamic nucleus and in the pituitary gonadotrophs (4). Knockout mouse technology by targeted disruption of the SF-1 gene has clearly demonstrated the major role of SF-1 in development. All animals died within a week of birth from adrenocortical insufficiency that could be prevented by steroid hormone replacement therapy (5). The adrenal glands and the gonads were absent in the knockout mice, explaining the hormonal defect. Furthermore, a male-to-female sex reversal of external genitalia was observed, since all the knockout mice had female genitalia irrespective of genetic sex. Therefore, SF-1 also plays an important role in sexual differentiation. This last finding might be