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Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039
We used
transgenic mice to identify cis-active regions of the human
pulmonary surfactant protein C (SP-C) gene that impart tissue-
and cell-specific expression in vivo in the lung.
Approximately 3.7 kb of genomic SP-C DNA upstream of the transcription
start site was sufficient to direct chloramphenicol acetyltransferase (CAT) reporter gene expression specifically in bronchiolar and alveolar epithelial cells of the lung. To further define
cis-active regulatory elements that mediate cell-specific
expression, we tested deletions of the parental 3.7-kb human SP-C
sequence in transgenic mice. Tissue CAT assays of mice generated with
truncations or overlapping internal deletions of the 3.7-kb construct
functionally map alveolar cell-specific regulatory elements to within
215 bp of the SP-C promoter. Analysis of SP-C promoter deletions
demonstrate that sequences between 3.7 kb and 1.9 kb
contain enhancer sequences that stimulate SP-C transgene
expression. In situ hybridization studies demonstrate that deletion of
the 1,910- to 215-bp region abolishes the ectopic
bronchiolar expression seen with the original 3.7-kb SP-C promoter
construct. Comparison of sequences from 215 to +1 bp identified
consensus binding sites for the homeodomain transcription factor
thyroid transcription factor-1 (TTF-1). Cotransfection assays of the
human 3.7-kb SP-C or 1,910- to 215-bp SP-C deletion construct with a TTF-1 expression plasmid demonstrates that TTF-1 transactivates the human SP-C gene. These results suggest that the TTF-1 cis-active sites are important in directing
cell-specific expression of the SP-C gene in vivo.
thyroid transcription factor-1; chloramphenicol acetyltransferase
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