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J. Biol. Chem., Vol. 280, Issue 48, 40032-40040, December 2, 2005

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Disruption of the Phosphatidylserine Decarboxylase Gene in Mice Causes Embryonic Lethality and Mitochondrial Defects^*

Rineke Steenbergen1, Terry S. Nanowski2, Anne Beigneux, Agnes Kulinski, Stephen G. Young, and Jean E. Vance3

From the Canadian Institutes for Health Research Group on the Molecular and Cell Biology of Lipids and Department of Medicine, University of Alberta, Edmonton, Alberta T6G 2S2, Canada and the Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095

Most of the phosphatidylethanolamine (PE) in mammalian cells is synthesized by two pathways, the CDP-ethanolamine pathway and the phosphatidylserine (PS) decarboxylation pathway, the final steps of which operate at spatially distinct sites, the endoplasmic reticulum and mitochondria, respectively. We investigated the importance of the mitochondrial pathway for PE synthesis in mice by generating mice lacking PS decarboxylase activity. Disruption of Pisd in mice resulted in lethality between days 8 and 10 of embryonic development. Electron microscopy of Pisd^-/- embryos revealed large numbers of aberrantly shaped mitochondria. In addition, fluorescence confocal microscopy of Pisd^-/- embryonic fibroblasts showed fragmented mitochondria. PS decarboxylase activity and mRNA levels in Pisd^+/- tissues were approximately one-half of those in wild-type mice. However, heterozygous mice appeared normal, exhibited normal vitality, and the phospholipid composition of livers, testes, brains, and of mitochondria isolated from livers, was the same as in wild-type littermates. The amount and activity of a key enzyme of the CDP-ethanolamine pathway for PE synthesis, CTP:phosphoethanolamine cytidylyltransferase, were increased by 35-40 and 100%, respectively, in tissues of Pisd^+/- mice, as judged by immunoblotting; PE synthesis from [³H]ethanolamine was correspondingly increased in hepatocytes. We conclude that the CDP-ethanolamine pathway in mice cannot substitute for a lack of PS decarboxylase during development. Moreover, elimination of PE production in mitochondria causes fragmented, misshapen mitochondria, an abnormality that likely contributes to the embryonic lethality.

Received for publication, June 15, 2005 , and in revised form, September 7, 2005.

The nucleotide sequence of the Mouse PS Carboxylase Gene (Pisd) reported in this paper has been submitted to the Mouse Genome Informatics Data Base (www.informatics.jax.org) with accession number ID: MGI 2445114.

^* This research was supported by grants from the Canadian Institutes for Health Research (CIHR) and the Heart and Stroke Foundation of Canada (HSFC) (to J. E. V.). The project was supported by an NHLBI, National Institutes of Health-funded program in genomics applications "BayGenomics" (HL66621, HL66600). 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 Recipient of a postdoctoral fellowship from the Alberta Heritage Foundation for Medical Research.

² A CIHR/HSFC Strategic Training Fellow in Stroke, Cardiovascular, Obesity, Lipid, Atherosclerosis Research (SCOLAR).

³ To whom correspondence should be addressed: 332 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada. Tel.: 780-492-7250; Fax: 780-492-3383; E-mail: jean.vance{at}ualberta.ca.

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