THE NUCLEAR RECEPTOR STEROIDOGENIC FACTOR-1 ACTS AT MULTIPLE LEVELS OF THE REPRODUCTIVE AXIS

Steroidogenic factor 1 (SF-1), an orphan nuclear receptor, regulates t he enzymes that produce sex steroids, and disruption of the Ftz-F1 gen e encoding SF-1 precludes adrenal and gonadal development. We now stud y the role of SF-1 at other levels of the hypothalamic/pituitary/gonad al axis. In Ftz-F1-disrupted mice, immunohistochemical analyses with a ntibodies against pituitary trophic hormones showed a selective loss o f gonadotrope-specific markers, supporting the role of SF-1 in gonadot rope function. In situ hybridization analyses confirmed these results; pituitaries from Ftz-F1-disrupted mice lacked transcripts for three g onadotrope-specific markers (LH beta, FSH beta, and the receptor for g onadotropin-releasing hormone), whereas they exhibited decreased but d etectable expression of the alpha-subunit of glycoprotein hormones. SF -1 transcripts in the developing mouse pituitary, which first became d etectable at embryonic day 13.5-14.5, preceded the appearance of FSH b eta and LH beta transcripts. In adult rat pituitary cells, SF-1 transc ripts colocalized with immunoreactivity for the gonadotrope-specific L H. finally, SF-1 interacted with a previously defined promoter element in the glycoprotein hormone alpha-subunit gene, providing a possible mechanism for the impaired gonadotropin expression in Ftz-F1-disrupted mice. These studies establish novel roles of this orphan nuclear rece ptor in reproductive function.