Transcriptional Regulation of Lung Cytidylyltransferase in Developing Transgenic Mice

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 (CCTα). To investigate the molecular basis for developmental activation of CCTα, we analyzed expression of endogenous CCTα and a reporter gene, β-galactosidase, in fetal, newborn, and adult promoter-reporter transgenic mice. Transgenics harboring ∼ 2 kb of the CCTα promoter linked upstream of a β-galactosidase reporter gene displayed relatively high expression in distal lung epithelia. Endogenous lung CCTα and β-galactosidase activities, protein content, and transcript levels displayed maximal expression within the newborn period. CCTα and β-galactosidase activities and enzyme levels increased with time in cultured fetal lung explants isolated from transgenics. Transfectional analysis using CCTα 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 CCTα gene