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J. Biol. Chem., Vol. 281, Issue 28, 19655-19664, July 14, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/28/19655    most recent M601195200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Borchert, A. Articles by Kuhn, H. Search for Related Content PubMed PubMed Citation Articles by Borchert, A. Articles by Kuhn, H. Social Bookmarking                      What's this?

The Role of Phospholipid Hydroperoxide Glutathione Peroxidase Isoforms in Murine Embryogenesis^*

Astrid Borchert, Chi Chiu Wang^¶, Christoph Ufer, Heike Schiebel, Nicolai E. Savaskan^||, and Hartmut Kuhn¹

From the Institute of Biochemistry, University Medicine Berlin-Charité, Monbijoustrasse 2, D-10117 Berlin, Germany, Li Ka Shing Institute of Health Sciences and ^¶Department of Obstetrics and Gynaecology, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, and the ^||Division of Cellular Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Phospholipid hydroperoxide glutathione peroxidase (GPx4) is a selenocysteine-containing enzyme, and three different isoforms (cytosolic, mitochondrial, and nuclear) originate from the GPx4 gene. Homozygous GPx4-deficient mice die in utero at midgestation, since they fail to initiate gastrulation and do not develop embryonic cavities. To investigate the biological basis for embryonic lethality, we first explored expression of the GPx4 in adult murine brain and found expression of the protein in cerebral neurons. Next, we profiled mRNA expression during the time course of embryogenesis (embryonic days 6.5-17.5 (E6.5-17.5)) and detected mitochondrial and cytosolic mRNA species at high concentrations. In contrast, the nuclear isoform was only expressed in small amounts. Cytosolic GPx4 mRNA was present at constant levels (about 100 copies per 1000 copies of glyceraldehyde-3-phosphate dehydrogenase mRNA), whereas nuclear and mitochondrial isoforms were down-regulated between E14.5 and E17.5. In situ hybridization indicated expression of GPx4 isoforms in all developing germ layers during gastrulation and in the somite stage in the developing central nervous system and in the heart. When we silenced expression of GPx4 isoforms during in vitro embryogenesis using short interfering RNA technology, we observed that knockdown of mitochondrial GPx4 strongly impaired segmentation of rhombomeres 5 and 6 during hindbrain development and induced cerebral apoptosis. In contrast, silencing expression of the nuclear isoform led to retardations in atrium formation. Taken together, our data indicate specific expression of GPx4 isoforms in embryonic brain and heart and strongly suggest a role of this enzyme in organogenesis. These findings may explain in part intrauterine lethality of GPx4 knock-out mice.

Received for publication, February 7, 2006 , and in revised form, May 5, 2006.

^* This work was supported in part by Deutsche Forschungsgemeinschaft Grant Ku 961/6-3, SA1041/3-2, European Commission Grant FP6, LSHM-CT-2004-0050333 (to H. K.), a Medicine/Application Solution Transgenic Platform (ASTP) special equipment grant, a grant from the Li Ka Shing Institute of Health Sciences (to C. C. W.), and a grant from the International Human Frontier Science Program Organization (to N. E. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 49-30-450-528040; Fax: 49-30-450-528905; E-mail: hartmut.kuehn{at}charite.de.

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