A 278 bp region just upstream of the human CYP19 (aromatase) gene mediates ovary-specific expression in transgenic mice.

Abstract

In humans, the CYP19 gene, which encodes aromatase P450, is expressed in a number of tissues including gonads, adipose, bone, and placenta. The 5'-untranslated regions (UTR) of CYP19 mRNA transcripts in these tissues are encoded by different tissue-specific first exons, which are alternatively spliced onto a common site just upstream of the start site of translation in exon II. In ovary, the 5'-UTR of CYP19 transcripts is encoded by exon IIa, which lies just upstream of exon II. To map genomic sequences required for ovary-specific CYP19 expression, fusion genes containing 2700, 278 and 43 bp of exon IIa 5'-flanking DNA linked to the human growth hormone (hGH) gene, as reporter, were introduced into mice. CYP19(IIa)-2700:hGH and CYP19(IIa)-278:hGH transgenes were expressed at high levels in ovaries of transgenic mice, whereas, ovarian expression of CYP19(IIa)-43:hGH was undetectable. In the majority of mice carrying the CYP19(IIa)-2700:hGH and CYP19(IIa)-278:hGH fusion genes, transgene expression was ovary-specific, indicating that genomic sequences within 278 bp region mediate ovary-specific expression. Expression of CYP19(IIa)-2700:hGH and CYP19(IIa)-278:hGH fusion genes was detected in ovarian granulosa and luteal cells, as well as in luteinized interstitial cells in mice during the estrous cycle. The most intense hGH immunostaining was observed in corpora lutea. This pattern of transgene expression is similar to that of aromatase in women where both granulosa and luteal cells express aromatase during the menstrual cycle. These findings suggest that transgenic mice provide an excellent model for analyzing genomic regions that mediate ovary-specific expression of the human CYP19 gene.