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Molecular and Cellular Biology, April 2005, p. 3357-3363, Vol. 25, No. 8
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.8.3357-3363.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Early Embryonic Lethality in Mice with Targeted Deletion of the CTP:Phosphocholine Cytidylyltransferase {alpha} Gene (Pcyt1a)

Limin Wang,1 Susan Magdaleno,2 Ira Tabas,3 and Suzanne Jackowski1*

Departments of Infectious Diseases,1 Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee,2 Departments of Medicine, Anatomy and Cell Biology, and Physiology and Cellular Biophysics, Columbia University, New York, New York3

Received 17 November 2004/ Returned for modification 15 December 2004/ Accepted 22 January 2005

CTP:phosphocholine cytidylyltransferase (CCT) catalyzes a rate-controlling step in the biosynthesis of phosphatidylcholine (PtdCho). Multiple CCT isoforms, CCT{alpha}, CCTß2, and CCTß3, 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 CCTß 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 CCTß and PtdEtn N-methyltransferase transcripts. In contrast, enzymatic and real-time PCR data revealed that CCTß (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 Pcyt1a+/+ 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.

* Corresponding author. Mailing address: St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794. Phone: (901) 495-3494. Fax: (901) 495-3099. E-mail: suzanne.jackowski{at}stjude.org.

Molecular and Cellular Biology, April 2005, p. 3357-3363, Vol. 25, No. 8
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.8.3357-3363.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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