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