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J. Biol. Chem., Vol. 283, Issue 1, 202-212, January 4, 2008

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Phosphatidylcholine Biosynthesis via CTP:Phosphocholine Cytidylyltransferase β2 Facilitates Neurite Outgrowth and Branching^*

Jodi M. Carter¹², Laurent Demizieux^¶23, Robert B. Campenot^||, Dennis E. Vance⁴, and Jean E. Vance^¶5

From the Canadian Institutes of Health Research Group on the Molecular and Cell Biology of Lipids and the Departments of Biochemistry, ^||Cell Biology, and ^¶Medicine, University of Alberta, Edmonton, Alberta T6G 2S2, Canada

Hallmarks of neuronal differentiation are neurite sprouting, extension, and branching. We previously showed that increased expression of CTP:phosphocholine cytidylyltransferase β2 (CTβ2), an isoform of a key phosphatidylcholine (PC) biosynthetic enzyme, accompanies neurite outgrowth (Carter, J. M., Waite, K. A., Campenot, R. B., Vance, J. E., and Vance, D. E. (2003) J. Biol. Chem. 278, 44988–44994). CTβ2 mRNA is highly expressed in the brain. We show that CTβ2 is abundant in axons of rat sympathetic neurons and retinal ganglion cells. We used RNA silencing to decrease CTβ2 expression in PC12 cells differentiated by nerve growth factor. In CTβ2-silenced cells, numbers of primary and secondary neurites were markedly reduced, suggesting that CTβ2 facilitates neurite outgrowth and branching. However, the length of individual neurites was significantly increased, and the total amount of neuronal membrane was unchanged. Neurite branching of PC12 cells is known to be inhibited by activation of Akt and promoted by the Akt inhibitor LY294002. Our experiments showed that LY294002 increases neurite sprouting and branching in control PC12 cells but not in CTβ2-deficient cells. CTβ2 was not phosphorylated in vitro by Akt. However, inhibition of Cdk5 by roscovitine blocked CTβ2 phosphorylation and reduced neurite outgrowth and branching. These results highlight the importance of CTβ2 in neurons for promoting neurite outgrowth and branching and represent the first identification of a lipid biosynthetic enzyme that facilitates these functions.

Received for publication, August 7, 2007 , and in revised form, October 31, 2007.

^* This work was supported by operating grants from the Canadian Institutes for Health Research (CIHR). 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 Supported by studentships from the Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research.

² Both authors contributed equally to this work.

³ Supported by a CIHR/HSFC strategic training grant in stroke, cardiovascular disease, obesity, lipids, and atherosclerosis research.

⁴ Scientist of the Alberta Heritage Foundation for Medical Research and holder of the Canada Research Chair in Molecular and Cell Biology of Lipids.

⁵ To whom correspondence should be addressed. Tel.: 780-492-7250; Fax: 780-492-3383; E-mail: jean.vance{at}ualberta.ca.

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