Early embryonic lethality caused by disruption of the gene for choline kinase alpha, the first enzyme in phosphatidylcholine biosynthesis.
Choline kinase alpha (CK-alpha) 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-alpha with an embryonic stem cell line containing an insertional mutation in the gene for CK-alpha (Chka). Embryos homozygous for the mutant Chka allele were recovered at the blastocyst stage, but not at embryonic day 7.5, indicating that CK-alpha 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 approximately 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 approximately 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.
Wu
Gengshu
G
Canadian Institutes of Health Research Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton T6G 2S2, Canada.
Aoyama
Chieko
C
Canadian Institutes of Health Research Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton T6G 2S2, Canada.
Young
Stephen G
SG
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095.
Vance
Dennis E
DE
Canadian Institutes of Health Research Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton T6G 2S2, Canada. Electronic address: dennis.vance@ualberta.ca.
D000818:Animals; D002794:Choline / Q000378:metabolism; D002797:Choline Kinase / Q000235:genetics* / Q000378:metabolism; D019916:Choline-Phosphate Cytidylyltransferase / Q000378:metabolism; D003433:Crosses, Genetic; D020964:Embryo Loss / Q000201:enzymology*; D004795:Enzyme Stability; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006579:Heterozygote; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D010713:Phosphatidylcholines / Q000096:biosynthesis*; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013737:Testis / Q000201:enzymology
D010713:Phosphatidylcholines; D012333:RNA, Messenger; D050918:Phosphatidylethanolamine N-Methyltransferase; C526451:Chka protein, mouse; D002797:Choline Kinase; D019916:Choline-Phosphate Cytidylyltransferase; D002794:Choline