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Transcriptional Regulation of Lung Cytidylyltransferase in Developing Transgenic Mice

Department of Internal Medicine, Department of Biochemistry, and the Department of Veterans Affairs Medical Center, the University of Iowa Carver College of Medicine, Iowa City, Iowa; and Amaxa, Inc., Gaithersburg, Maryland

Correspondence and requests for reprints should be addressed to Rama K. Mallampalli, M.D., Pulmonary & Critical Care Division, C-33K, GH, Departments of Internal Medicine & Biochemistry, University of Iowa College of Medicine, Iowa City, IA 52242. E-mail: rama-mallampalli{at}uiowa.edu

Lung development is associated with a surge in surfactant phosphatidylcholine (PC) production to prepare the newborn for extrauterine breathing. This process is associated with a marked increase in the activity of the rate-regulatory surfactant enzyme, CTP:phosphocholine cytidylyltransferase (CCT). To investigate the molecular basis for developmental activation of CCT, we analyzed expression of endogenous CCT and a reporter gene, -galactosidase, in fetal, newborn, and adult promoter-reporter transgenic mice. Transgenics harboring 2 kb of the CCT promoter linked upstream of a -galactosidase reporter gene displayed relatively high expression in distal lung epithelia. Endogenous lung CCT and -galactosidase activities, protein content, and transcript levels displayed maximal expression within the newborn period. CCT and -galactosidase activities and enzyme levels increased with time in cultured fetal lung explants isolated from transgenics. Transfectional analysis using CCT promoter–reporter constructs in developing rat type II cells revealed that a region encompassing –169/+71 contained the DNA elements required for perinatal activation. The studies demonstrate that developmental induction of surfactant phospholipid is due, at least in part, to transcriptional activation of the CCT gene.

Key Words: surfactant • development • pulmonary