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J. Biol. Chem., Vol. 283, Issue 19, 12888-12897, May 9, 2008

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Defining the Importance of Phosphatidylserine Synthase-1 (PSS1)

Unexpected Viability of PSS1-Deficient Mice^*

Devi Arikketh, Randy Nelson^¶, and Jean E. Vance¹

From the Group on the Molecular and Cell Biology of Lipids and Departments of Medicine and ^¶Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada

Phosphatidylserine (PS) is a quantitatively minor, but physiologically important, phospholipid in mammalian cells. PS is synthesized by two distinct base-exchange enzymes, PS synthase-1 (PSS1) and PS synthase-2 (PSS2), that are encoded by different genes. PSS1 exchanges serine for choline of phosphatidylcholine, whereas PSS2 exchanges ethanolamine of phosphatidylethanolamine for serine. We previously generated mice lacking PSS2 (Bergo, M. O., Gavino, B. J., Steenbergen, R., Sturbois, B., Parlow, A. F., Sanan, D. A., Skarnes, W. C., Vance, J. E., and Young, S. G. (2002) J. Biol. Chem. 277, 47701–47708) and found that PSS2 is not required for mouse viability. We have now generated PSS1-deficient mice. In light of the markedly impaired survival of Chinese hamster ovary cells lacking PSS1 we were surprised that PSS1-deficient mice were viable, fertile, and had a normal life span. Total serine-exchange activity (contributed by PSS1 and PSS2) in tissues of Pss1^–/– mice was reduced by up to 85%, but except in liver, the PS content was unaltered. Despite the presumed importance of PS in the nervous system, the rate of axonal extension of PSS1-deficient neurons was normal. Intercrosses of Pss1^–/– mice and Pss2^–/– mice yielded mice with three disrupted Pss alleles but no double knockout mice. In Pss1^–/–/Pss2^–/– and Pss1^–/–/Pss2^–/– mice, serine-exchange activity was reduced by 65–91%, and the tissue content of PS and phosphatidylethanolamine was also decreased. We conclude that (i) elimination of either PSS1 or PSS2, but not both, is compatible with mouse viability, (ii) mice can tolerate as little as 10% of normal total serine-exchange activity, and (iii) mice survive with significantly reduced PS and phosphatidylethanolamine content.

Received for publication, January 28, 2008 , and in revised form, March 3, 2008.

^* This work was supported by an operating grant from the Canadian Institutes for Health Research (CIHR) and a CIHR/Heart and Stroke Foundation strategic training grant in stroke, cardiovascular disease, obesity, lipids, and atherosclerosis research (SCOLAR). 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: Dept. of Medicine, 328 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Tel.: 780-492-7250; Fax: 780-492-3383; E-mail: jean.vance{at}ualberta.ca.

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