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J. Biol. Chem., Vol. 283, Issue 3, 1456-1462, January 18, 2008

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Early Embryonic Lethality Caused by Disruption of the Gene for Choline Kinase , the First Enzyme in Phosphatidylcholine Biosynthesis^*

Gengshu Wu¹, Chieko Aoyama¹, Stephen G. Young, and Dennis E. Vance²

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

Choline kinase (CK-) is one of two mammalian enzymes that catalyze the phosphorylation of choline to phosphocholine in the biosynthesis of the major membrane phospholipid, phosphatidylcholine. We created mice lacking CK- with an embryonic stem cell line containing an insertional mutation in the gene for CK- (Chka). Embryos homozygous for the mutant Chka allele were recovered at the blastocyst stage, but not at embryonic day 7.5, indicating that CK- is crucial for the early development of mouse embryos. Heterozygous mutant mice (Chka^+/-) appeared entirely normal in their embryonic development and gross anatomy, and they were fertile. Although choline kinase activity was decreased by 30%, the amount of phosphatidylcholine in cells and the levels of other enzymes involved in phosphatidylcholine biosynthesis were unaffected. Phosphatidylcholine biosynthesis measured by choline incorporation into hepatocytes was also not compromised in Chka^+/- mice. Enhanced levels of choline and attenuated levels of phosphocholine were observed in both the livers and testes of Chka^+/- mice. Triacylglycerol and cholesterol ester were elevated 2-fold in the livers, whereas neutral lipid profiles in plasma were similar in Chka^+/- and wild-type (Chka^+/+) mice. Thus, Chka is an essential gene for early embryonic development, but adult mice do not require full expression of the gene for normal levels of phosphatidylcholine.

Received for publication, October 23, 2007 , and in revised form, November 19, 2007.

^* This work was supported by a grant from the Canadian Institutes of Health Research and by BayGenomics, a Program for Genomics Applications from the National Institutes of Health NHLBI Grant UO1 HL66621. 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: HMRC 320, Edmonton T6G 2S2, Canada. E-mail: dennis.vance{at}ualberta.ca.

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