Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side-chain-cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids

• Published in: Proceedings of the National Academy of Sciences - PNAS 1995-11, Vol.92 (24), p.10939-10943
• Main Authors: Sadovsky, Y, Crawford, P A, Woodson, K G, Polish, J A, Clements, M A, Tourtellotte, L M, Simburger, K, Milbrandt, J
• Format: Article
• Language: English
• Subjects: Adrenal Cortex Hormones - blood; Adrenal Glands - abnormalities; Animals; Base Sequence; Cholesterol Side-Chain Cleavage Enzyme - metabolism; DNA Primers - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Fushi Tarazu Transcription Factors; Gene Expression; Gonads - abnormalities; Homeodomain Proteins; Mice; Mice, Knockout; Molecular Sequence Data; Placenta - metabolism; Receptors, Cytoplasmic and Nuclear - deficiency; Repressor Proteins - genetics; RNA, Messenger - genetics; Sequence Alignment; Sequence Homology, Amino Acid; Steroidogenic Factor 1; Transcription Factors - physiology; Zinc Fingers
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.92.24.10939

The orphan nuclear receptor steroidogenic factor 1 (SF-1) is expressed in the adrenal cortex and gonads and regulates the expression of several P450 steroid hydroxylases in vitro. We examined the role of SF-1 in the adrenal glands and gonads in vivo by a targeted disruption of the mouse SF-1 gene. All SF-1-deficient mice died shortly after delivery. Their adrenal glands and gonads were absent, and persistent Mullerian structures were found in all genotypic males. While serum levels of corticosterone in SF-1-deficient mice were diminished, levels of adrenocorticotropic hormone (ACTH) were elevated, consistent with intact pituitary corticotrophs. Intrauterine survival of SF-1-deficient mice appeared normal, and they had normal serum level of corticosterone and ACTH, probably reflecting transplacental passage of maternal steroids. We tested whether SF-1 is required for P450 side-chain-cleavage enzyme (P450scc) expression in the placenta, which expresses both SF-1 and P450scc, and found that in contrast to its strong activation of the P450scc gene promoter in vitro, the absence of SF-1 had no effect on P450scc mRNA levels in vivo. Although the region targeted by our disruption is shared by SF-1 and by embryonal long terminal repeat-binding protein (ELP), a hypothesized alternatively spliced product, we believe that the observed phenotype reflects absent SF-1 alone, as PCR analysis failed to detect ELP transcripts in any mouse tissue, and sequences corresponding to ELP are not conserved across species. These results confirm that SF-1 is an important regulator of adrenal and gonadal development, but its regulation of steroid hydroxylase expression in vivo remains to be established.