D

Fig. 2. Adrenal and gonadal agenesis in SF-1 knockout mice. SF-1 knockout mice and wild-type littermates were killed and the genitourinary tracts were dissected. (A) SF-1 knockout female; (B) Wild-type female; (C) SF-1 knockout male; (D). Wild-type male. k, kidney; a, adrenal; o, ovary; od, oviduct; e, epididymis; t, testis. Reprinted with permission from ref. 23.

and 18 for discussions of approaches currently being taken to extend our understanding of SF-1's roles in endocrine development and function.)

With respect to neurosteroids, we understand very little about the processes that regulate their biosynthesis. Unlike adrenocortical and gonadal steroids, whose production is controlled predominantly by pituitary trophic hormones, the factors that modulate neurosteroid production have yet to be defined. Similarly, the factors that determine tissue-selective expression of steroidogenic enzymes within the brain are poorly understood. SF-1 expression in the brain is restricted to neurons of the VMH, whereas steroidogenic enzymes are distributed more widely and are produced by glial cells. Thus, although SF-1 may contribute to neurosteroid biosynthesis—especially to the extent that biologically active neurosteroids are derived from adrenocortical and gonadal precursors—it is unlikely that SF-1 regulates steroidogenic enzyme expression in presumptive sites of de novo neurosteroid biosynthesis. This, then, raises the question of what mechanisms regulate steroid hydroxylase expression at nonadrenal and gonadal sites. Conceiv-

Fig. 3. SF-1 knockout mice have agenesis of the VMH. A drawing of the relevant neuroanatomy of the mouse hypothalamus is shown (upper left). Serial coronal sections from wild-type (lower left) and SF-1 knockout male (lower right) and female (upper right) mice were stained with cresyl violet and analyzed histologically. ME, median eminence; Arc, arcuate nucleus; VMH, ventromedial hypothalamic nucleus; DMH, dorsomedial hypothalamic nucleus; Do, dorsal hypothalamic nucleus; mt, mammilothalamic tract; 3 V, Third ventricle. Modified with permission from ref. 31.

Fig. 3. SF-1 knockout mice have agenesis of the VMH. A drawing of the relevant neuroanatomy of the mouse hypothalamus is shown (upper left). Serial coronal sections from wild-type (lower left) and SF-1 knockout male (lower right) and female (upper right) mice were stained with cresyl violet and analyzed histologically. ME, median eminence; Arc, arcuate nucleus; VMH, ventromedial hypothalamic nucleus; DMH, dorsomedial hypothalamic nucleus; Do, dorsal hypothalamic nucleus; mt, mammilothalamic tract; 3 V, Third ventricle. Modified with permission from ref. 31.

ably, different promoters direct their expression at various sites (e.g., the adrenal cortex and gonads vs sites such as the brain and placenta), with only the promoter expressed in the adrenal cortex and gonads utilizing SF-1-responsive elements. This mechanism apparently underlies aromatase expression in different tissues (33). Alternatively, the same promoter may be active in multiple sites, with distinct promoter elements directing transcription in each tissue. In this case, SF-1-responsive elements would regulate expression in the adrenal cortex and gonads, whereas other elements—interacting with yet-to-be-identified transcriptional regulatory proteins—would regulate transcription in sites such as the placenta and brain. Ongoing efforts to explore these questions should provide novel insights into the complex regulation of steroid hormone production, both in classical steroidogenic tissues such as the adrenal cortex and gonads and in the "non-classical" sites such as the brain. One intriguing possibility is that a better definition of the promoter elements that direct steroid hydroxylase expression, coupled with techniques for targeted gene modification, may provide a means to abolish de novo production of neurosteroids by blocking selectively steroidogenic enzyme expression in the brain. This would provide a powerful model system to elucidate the roles of neurosteroids in various physiological processes.

Table 1

Sites of Action and Target Genes for SF-1

Table 1

Sites of Action and Target Genes for SF-1

VMH:

?

Gonadotropes:

a-subunit of glycoprotein hormones

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