Profiles of SF1 Expression

As suggested by the initial gel mobility shift experiments, Northern-blotting analyses showed that SF-1 was selectively expressed in steroidogenic cells of the adrenal cortex and gonads (5). Using more sensitive reverse transcription-polymerase chain reaction (RT-PCR) assays, SF-1 transcripts also were detected in the pituitary, placenta, brain, and spleen (16). To identify the specific cell types expressing SF-1, several laboratories used in situ hybridization and immunohistochemical analyses to localize SF-1 expression (reviewed in 17,18). In these studies, SF-1 expression generally correlated with known sites of primary steroidogenesis, including adrenocortical cells, testicular Leydig cells, and ovarian theca and granulosa cells. These findings again were consistent with an important role of SF-1 in tissue-specific expression of the steroid hydroxylases. Surprisingly, SF-1 was not expressed at appreciable levels in the placenta, despite its known role in steroid hormone production. Finally, as predicted by the RT-PCR studies, SF-1 was also expressed in other cells, including pituitary gonadotropes and neurons comprising

Fig. 1. Ontogeny of SF-1 expression. The ontogeny of expression of SF-1 in developing mouse embryos is summarized schematically. (+), SF-1 transcripts were detected; (—), SF-1 transcripts were not detected. The arrows denote the approximate transition times between the different developmental stages. UR, urogenital ridge. Reprinted with permission from ref. 17.

Fig. 1. Ontogeny of SF-1 expression. The ontogeny of expression of SF-1 in developing mouse embryos is summarized schematically. (+), SF-1 transcripts were detected; (—), SF-1 transcripts were not detected. The arrows denote the approximate transition times between the different developmental stages. UR, urogenital ridge. Reprinted with permission from ref. 17.

the VMH. These findings suggested that SF-1 might also play additional roles beyond regulating the steroid hydroxylases.

To delineate potential roles of SF-1 in mammalian development, similar approaches were used to examine the spatial and temporal profile of SF-1 expression during embryogenesis (19-22). These studies defined intriguing profiles of SF-1 expression (Fig. 1). SF-1 transcripts were detected in the adrenal primordium and gonads from the inception of their development. The initiation of SF-1 expression in these sites before the onset of steroid hydroxylase expression is consistent with the model that SF-1 activates steroid hydroxylase gene expression.

The earliest detectable sign of gonadogenesis begins in mice at ~E9, when the intermediate mesoderm condenses into a urogenital ridge that ultimately contributes to the gonads, adrenal glands, and kidneys. Up until ~E12.5, testes and ovaries cannot be distinguished histologically, and are referred to as indifferent or bipotential gonads. Thereafter, formation of the testicular cords, which contain fetal Sertoli cells that produce Müllerian-inhibiting substance (MIS) and primordial germ cells, allows the testis to be recognized. Interspersed around these cords is the interstitial region, which contains the steroidogenic Leydig cells where androgens are produced. SF-1 initially was expressed in the indifferent gonads of all embryos, and this expression persisted throughout the indifferent stage. Coincident with sexual differentiation and the formation of the testicular cords at E12.5, SF-1 expression increased in the testes but was extinguished in ovaries. Unexpectedly, although SF-1 in the adult testis is expressed primarily by the steroidogenic Leydig cells, SF-1 transcripts were detected in both compartments of the fetal testes: the interstitial region and the testicular cords.

Consistent with the RT-PCR analyses of adult tissues (16), SF-1 transcripts also were detected in the embryonic diencephalon, which ultimately contributes to the endocrine hypothalamus, and the anterior pituitary gland. These findings suggested that SF-1 acts at multiple levels of the hypothalamic-pituitary-steroidogenic organ axis, playing roles that extend beyond regulating the expression of steroidogenic enzymes.

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