|Clevidence D E|
|Overdier D C|
|Peterson R S|
|Paulson K E|
|Costa R H|
Submitted to: Developmental Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/20/1994
Publication Date: N/A
Citation: N/A Interpretive Summary: The development of the lung is highly complex and involves the specialization of many different kinds of cells. In this paper we show that several new proteins are present in a specific, specialized lung cell. Furthermore, we show that these proteins control surfactant, a protein which is important in lung function.
Technical Abstract: The hepatocyte nuclear factor 3 (HNF-3)/forkhead (fkh) proteins consist of an extensive family of tissue-specific and developmental gene regulators which share homology within the winged helix DNA binding motif. We report on the isolation of a new member, HFH-8, from lung cDNA libraries and the derivation of the complete amino acid sequences for the HFH-8 protein as well as the previously identi- fied HFH-1 and HFH-4 proteins. In situ hybridization with HNF-3, HFH-4 and HFH-8 probes in adult lung demonstrate that the HNF-3/fkh cellular expression patterns are regionally specified. Whereas HNF-3alpha and HNF-3beta are normally coexpressed in the hepatocyte, their expression patterns in lung are different. The HNF-3alpha and HFH-4 gene are coexpressed in the bronchiolar epithelium (clara cells), whereas the HNF-3beta probe exhibits prominent hybridization in the smooth muscle surrounding artioles and bronchioles. In contrast, HFH-8 probes labeled the type II pneumocyte cells lining the respiratory surfaces of terminal bronchioles and alveolar sac. We have identified an HNF-3 consensus DNA binding sequence in the proximal surfactant protein B (SPB) promoter region (SPB-f2, -78 to -88). SPB gene transcription is restricted to bronchiolar and alveolar epithelium which colocalizes with the expres- sion pattern of the HNF-3alpha and HFH-8 genes respectively. We show that the SBP-f2 sequence is recognized by both HNF-3a and HFH-8 proteins and that these cDNA expression vectors activate the SPB promoter in cotransfection assays through the HNF-3 consensus sequence. Our results suggest that SPB promoter activity is regulated by HNF-3alpha and HFH-8 proteins in a cell type-specific manner.