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Molecular and Cellular Biology, February 2003, p. 916-922, Vol. 23, No. 3
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.3.916-922.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Absence of Mitochondrial Thioredoxin 2 Causes Massive Apoptosis, Exencephaly, and Early Embryonic Lethality in Homozygous Mice

Larisa Nonn,* Ryan R. Williams, Robert P. Erickson, and Garth Powis*

Arizona Cancer Center, University of Arizona, Tucson, Arizona 85714-5024

Received 13 September 2002/ Returned for modification 2 October 2002/ Accepted 7 November 2002

Thioredoxin 2 (Trx-2) is a small redox protein containing the thioredoxin active site Trp-Cys-Gly-Pro-Cys that is localized to the mitochondria by a mitochondrial leader sequence and encoded by a nuclear gene (Trx-2). Trx-2 plays an important role in cell viability and the regulation of apoptosis in vitro. To investigate the role of Trx-2 in mouse development, we studied the phenotype of mice that have the Trx-2 gene silenced by mutational insertion. Homozygous mutant embryos do not survive to birth and die after implantation at Theiler stage 15/16. The homozygous mutant embryos display an open anterior neural tube and show massively increased apoptosis at 10.5 days postcoitus and are not present by 12.5 days postcoitus. The timing of the embryonic lethality coincides with the maturation of the mitochondria, since they begin oxidative phosphorylation during this stage of embryogenesis. In addition, embryonic fibroblasts cultured from homozygous Trx-2-null embryos were not viable. Heterozygous mice are fertile and have no discernible phenotype visible by external observation, despite having decreased Trx-2 mRNA and protein. These results show that the mitochondrial redox protein Trx-2 is required for normal development of the mouse embryo and for actively respiring cells.

* Corresponding author. Mailing address: Arizona Cancer Center, University of Arizona, 1515 N. Campbell Ave., Tucson, AZ 85724-5024. Phone: (520) 626-6408. Fax: (520) 626-4848. E-mail: gpowis{at}azcc.arizona.edu.

Molecular and Cellular Biology, February 2003, p. 916-922, Vol. 23, No. 3
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.3.916-922.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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