Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 25, Issue 8, Pages 3357-3363Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.25.8.3357-3363.2005
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Funding
- NCI NIH HHS [P30 CA021765, CA 21765] Funding Source: Medline
- NIGMS NIH HHS [GM45737, R01 GM045737] Funding Source: Medline
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CTP:phosphocholine cytidylyltransferase (CCT) catalyzes a rate-controlling step in the biosynthesis of phosphatidylcholine (PtdCho). Multiple CCT isoforms, CCT alpha, CCT beta 2, and CCT beta 3, are encoded by two genes, Pcyt1a and Pcyt1b. The importance of CCT alpha in mice was investigated by deleting exons 5 and 6 in the Pcyt1a gene using the Cre-lox system. Pcyt1a(-/-) zygotes failed to form blastocysts, did not develop past embryonic day 3.5 (E3.5), and failed to implant. In situ hybridization in E11.5 embryos showed that Pcyt1a is expressed ubiquitously, with the highest level in fetal liver, and CCT alpha transcripts are significantly more abundant than transcripts encoding CCT beta or phosphatidylethanolamine (PtdEtn) N-methyl transferase, two other enzymes capable of producing PtdCho. Reduction of the CCT alpha transcripts in heterozygous E11.5 embryos was accompanied by upregulation of CCT beta and PtdEtn N-methyltransferase transcripts. In contrast, enzymatic and real-time PCR data revealed that CCT beta (Pcyt1b) expression is not upregulated to compensate for the reduction in CCT alpha expression in adult liver and other tissues from Pcyt1a(+/-) heterozygous mice. PtdCho biosynthesis measured by choline incorporation into isolated hepatocytes was not compromised in the Pcyt1a(+/-) mice. Liver PtdCho mass was the same in Peyt1a(+/+) and Pcyt1a(+/-) adult animals, but lung PtdCho mass decreased in the heterozygous mice. These data show that CCT alpha expression is required for early embryonic development, but that a 50% reduction in enzyme activity has little detectable impact on the operation of the CDP-choline metabolic pathway in adult tissues.
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