Tissue-specific transgenic knockdown of Fos-related antigen 2 (Fra-2) expression mediated by dominant negative Fra-2

Fos-related antigen 2 (Fra-2) is a member of the Fos family of immediate-ea rly genes, most of which are rapidly induced by second messengers, All memb ers of this family act by binding to AP-1 sites as heterodimeric complexes with other proteins. However, each appears to have a distinct role, The rol e and biology of Fra-2 are less well understood than those of its relatives c-Fos, Fra-1, and FosB; moreover, Fra-2 target genes remain largely unknow n, as does the basis of its selective effects on transcriptional activity, To pursue these issues, we created a transgenic rat line (NATDNF2) in which a dominant negative fra-2 (DNF2) gene is strongly expressed in the pineal gland; tissue selectivity was achieved by putting the DNF2 gene under the c ontrol of the rat arylalkylamine N-acetyltransferase (AANAT) regulatory reg ion, which targets gene expression to a very restricted set of tissues (pin eal gland much greater than retina), Expression of AANAT is normally turned on after the onset of darkness in the rat; as a result, pineal DNF2 expres sion occurs only at night. This was associated with marked suppression of t he nocturnal increase in fra-2 mRNA and protein Levels, indicating that DNF 2 expression inhibits downstream effects of Fra-2, including the maintenanc e of high levels of fra-2 gene expression. Analysis of 1,190 genes in the N ATDNF2 pineal gland, including the AANAT gene, identified two whose express ion is strongly linked to fra-2 expression: the genes encoding type II iodo thyronine deiodinase and nectadrin (CD24).