CHARACTERIZATION OF THE MOUSE FTZ-F1 GENE, WHICH ENCODES A KEY REGULATOR OF STEROID HYDROXYLASE GENE-EXPRESSION

The cytochrome P450 steroid hydroxylases are coordinately regulated by steroidogenic factor 1 (SF-1), a protein expressed selectively in ste roidogenic cells. Based on its expression in steroidogenic tissues and DNA-binding specificity, we isolated a putative SF-1 cDNA from an adr enocortical cDNA library. As evidence that this cDNA encodes SF-1, we now show that it is selectively expressed in steroidogenic cells, that an antiserum against its protein product specifically abolishes the S F-1-related gel-shift complex, and that its coexpression increases pro moter activity of the 21-hydroxylase 5'-flanking region in transfectio n experiments. Sequence analyses of the SF-1 cDNA revealed that it is the mouse homolog of fushi tarazu factor I (FTZ-F1), a nuclear recepto r that regulates the fushi tarazu homeobox gene in Drosophila. A secon d FTZ-F1 homolog, embryonal long terminal repeat-binding protein (ELP) , was recently isolated from embryonal carcinoma cells. SF-1 and ELP c DNAs are virtually identical for 1017 base pairs, including putative D NA-binding domains, but diverge at their 5'- and 3'-ends. One genomic clone contained both SF-1- and ELP-specific sequences, confirming thei r origin from a single gene. Characterization of this gene defined sha red exons encoding common regions and alternative promoters and 3'-exo ns leading to differences between the two FTZ-F1 transcripts. We used in situ hybridization with transcript-specific probes to study the ont ogeny of SF-1 and ELP expression. ELP transcripts were not detected fr om embryonic day 8 to adult, consistent with its previous isolation fr om embryonal carcinoma cells and its postulated role in early embryoni c development. In contrast, SF-1 transcripts were first detected at em bryonic day 12, when steroidogenic organs begin to develop and steroid ogenic enzymes are first expressed, and persisted thereafter at high l evels in adrenal glands and testis. Collectively, these studies establ ish that the mouse homolog of the FTZ-F1 gene generates developmentall y regulated transcripts, one of which encodes an essential regulator o f steroid hydroxylase gene expression.