Differential regulation of the human CYP11A1 promoter in mouse brain and adrenals.

CYP11A1 encodes the first enzyme of steroid biosynthesis, cytochrome P450scc. The expression of CYP11A1 in the nervous system allows neurosteroids to be synthesized de novo. In the classic steroidogenic tissues, adrenals and gonads, the key regulator controlling CYP11A1 expression is steroidogenic factor-1 (SF-1), but the transcriptional regulation of CYP11A1 in the brain is unclear. We recently used the 4.4-kb regulatory region of the human CYP11A1 gene to drive Cre recombinase expression in the diencephalon and midbrain. In this study, we characterized the regional-specific expression of Cre reporter in the SCC-Cre transgenic brain using a transient Cre/ROSA26R transgenic system. Mutation of either the upstream or proximal SF-1 binding site did not affect brain CYP11A1 promoter activity. The upstream SF-1 binding site, however, is required for CYP11A1 promoter function in the embryonic adrenals. The 3.8-kb promoter, like the 4.4-kb length promoter, directed Cre expression in the diencephalon, midbrain and olfactory epithelium, whereas Cre expression controlled by the 2.7-kb promoter was only observed in the caudal part of midbrain. This suggests that the 5'-flanking region between 3.8 and 2.7 kb contains a crucial element for activation of CYP11A1 promoter in the diencephalon, olfactory epithelium and the anterior part of midbrain. Thus we have identified regions of the promoter that control CYP11A1 expression in the brain and embryonic adrenals.

Human CYP11A1 promoter drives Cre recombinase expression in the brain in addition to adrenals and gonads.

The first step of steroid biosynthesis is catalyzed by cytochrome P450scc, encoded by CYP11A1. To achieve steroidogenic tissue-specific inactivation of genes in vivo by the Cre-loxP approach, we used the 4.4-kb regulatory region of the human CYP11A1 gene to drive Cre recombinase expression in the tissues that produce steroids. The resulting SCC-Cre mice express high levels of Cre in the adrenal cortex and gonads at the same sites as that for the endogenous CYP11A1 expression. In addition, Cre activity was found in the diencephalon and midbrain. In the developing brain, the Cre activity was first detected in the embryonic day 10.5. Our study is the first to show that the 4.4-kb CYP11A1 promoter is transcriptionally active in the brain in vivo.