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Molecular and Cellular Biology, May 2005, p. 3658-3669, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3658-3669.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Distal Sequence Element of the Selenocysteine tRNA Gene Is a Tissue-Dependent Enhancer Essential for Mouse Embryogenesis

Vincent P. Kelly,1 Takafumi Suzuki,2 Osamu Nakajima,2 Tsuyoshi Arai,1 Yoshitaka Tamai,1 Satoru Takahashi,3 Susumu Nishimura,1 and Masayuki Yamamoto2*

Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd.,1 ERATO Environmental Response Project and Center for Tsukuba Advanced Research Alliance,2 Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan3

Received 23 August 2004/ Returned for modification 20 September 2004/ Accepted 28 January 2005

Appropriate expression of the selenocysteine tRNA (tRNASec) gene is necessary for the production of an entire family of selenoprotein enzymes. This study investigates the consequence of disrupting an upstream enhancer region of the mouse tRNASec gene (Trsp) known as the distal sequence element (DSE) by use of a conditional repair gene targeting strategy, in which a 3.2-kb insertion was introduced into the promoter of the gene. In the absence of DSE activity, homozygous mice failed to develop in utero beyond embryonic day 7.5 and had severely decreased levels of selenoprotein transcript. Cre-mediated removal of the selection cassette recovered DSE regulation of Trsp, restoring wild-type levels of tRNASec expression and allowing the generation of viable rescued mice. Further analysis of targeted heterozygous adult mice revealed that the enhancer activity of the DSE is tissue dependent since, in contrast to liver, heart does not require the DSE for normal expression of Trsp. Similarly, in mouse cell lines we showed that the DSE functions as a cell-line-specific inducible element of tRNASec. Together, our data demonstrate that the DSE is a tissue-dependent regulatory element of tRNASec expression and that its activity is vital for sufficient tRNASec production during mouse embryogenesis.

* Corresponding author. Mailing address: Center for TARA, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan. Phone: 81-298-53-6158. Fax: 81-298-53-7318. E-mail: masi{at}tara.tsukuba.ac.jp.

Molecular and Cellular Biology, May 2005, p. 3658-3669, Vol. 25, No. 9
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.9.3658-3669.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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