Early embryonic lethality caused by disruption of the gene for choline kinase α, the first enzyme in phosphatidylcholine biosynthesis

Abstract

Choline kinase α (CK-α) 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-α with an embryonic stem cell line containing an insertional mutation in the gene for CK-α (Chka). Embryos homozygous for the mutant Chka allele were recovered at the blastocyst stage, but not at embryonic day 7.5, indicating that CK-α 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. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.