The Roles Of Sf1 In Vivo Knockout Mouse Studies

To define the roles of SF-1 in vivo, targeted gene disruption in embryonic stem cells was used to generate SF-1 knockout mice. Three groups independently produced SF-1 knockout mice, with generally congruent results. SF-1 knockout mice had female external genitalia irrespective of genetic sex, and died shortly after birth from adrenocortical insufficiency (23,24), supporting an essential role for SF-1 in androgen and corticosteroid biosynthesis. Surprisingly (Fig. 2), their adrenal glands and gonads were completely absent, revealing obligatory roles for SF-1 in the development of the primary steroidogenic tissues. Developmental studies showed that the earliest stages of adrenal and gonadal development still occurred in the absence of SF-1; subsequently, these structures manifested features characteristic of programmed cell death, and degenerated.

The expression of SF-1 in the anterior pituitary and hypothalamus suggested that the SF-1 knockout mice might also exhibit abnormalities at these sites. Consistent with this model, pituitaries of SF-1 knockout mice were deficient in immunoreactivity for luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (25,26), two separate markers of gonadotropes. Promoter analyses showed that SF-1 interacts with regulatory elements upstream of the genes encoding the a-subunit of glycoprotein hormones (25,27), the P-subunit of luteinizing hormone (28,29), and the GnRH receptor (30), thereby activating their expression. These findings linked SF-1 to gonadotrope function, and thus to a second level of the endocrine axis. Finally, the region corresponding to the VMH was absent from the hypothalamus of the knockout mice (Fig. 3) (26,31), also implicating SF-1 at the hypothalamic level. Similar to the adrenal gland and gonads, developmental studies suggested that early stages of VMH development were initiated in the absence of SF-1, with subsequent degeneration. This link between SF-1 and the VMH is intriguing because this hypothalamic nucleus has been linked to reproductive behavior in experimental model systems (32), again supporting an intimate relationship between SF-1 and reproduction.

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