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Molecular and Cellular Biology, June 2001, p. 3704-3713, Vol. 21, No. 11
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.11.3704-3713.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Tissue-Specific Transgenic Knockdown of Fos-Related Antigen 2 (Fra-2) Expression Mediated by Dominant Negative Fra-2

Martin Smith,1 Zoe Burke,1 Ann Humphries,1 Tim Wells,1 David Klein,2 David Carter,1 and Ruben Baler3,*

School of Bioscience, Cardiff University, Cardiff, United Kingdom,1 and Section on Neuroendocrinology, Laboratory of Developmental Neurobiology, National Institute of Child Health and Human Development,2 and Unit on Temporal Gene Expression, Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health,3 National Institutes of Health, Bethesda, Maryland 20892

Received 21 December 2000/Returned for modification 14 February 2001/Accepted 15 March 2001

Fos-related antigen 2 (Fra-2) is a member of the Fos family of immediate-early genes, most of which are rapidly induced by second messengers. All members 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 role 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 unknown, 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 control of the rat arylalkylamine N-acetyltransferase (AANAT) regulatory region, which targets gene expression to a very restricted set of tissues (pineal gland retina). Expression of AANAT is normally turned on after the onset of darkness in the rat; as a result, pineal DNF2 expression occurs only at night. This was associated with marked suppression of the nocturnal increase in fra-2 mRNA and protein levels, indicating that DNF2 expression inhibits downstream effects of Fra-2, including the maintenance of high levels of fra-2 gene expression. Analysis of 1,190 genes in the NATDNF2 pineal gland, including the AANAT gene, identified two whose expression is strongly linked to fra-2 expression: the genes encoding type II iodothyronine deiodinase and nectadrin (CD24).

* Corresponding author. Mailing address: Building 36, Room 2A-09, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 435-7522. Fax: (301) 402-1748. E-mail: abri{at}codon.nih.gov.

Molecular and Cellular Biology, June 2001, p. 3704-3713, Vol. 21, No. 11
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.11.3704-3713.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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