HNF-3/forkhead homologue-4 influences lung morphogenesis and respiratory epithelial cell differentiation in vivo

HNF-3/forkhead homologue 4 (HFH-4), a transcription factor of the winged he lix/forkhead family, is expressed in various tissues including lung, brain, oviduct, testis, and embryonic kidney. In order to test whether the tempor ospatial expression of HFH-4 influences lung morphogenesis, HFH-4 was expre ssed in lungs of transgenic mice under control of the surfactant protein C (SP-C) promoter. The morphology of the lungs from SP-C/HFH-4 embryos (day 1 8 postconception) was distinctly abnormal, and the severity of the alterati ons correlated with the level of transgene expression as detected by in sit u hybridization. At high levels of expression, HFH-4 altered epithelial cel l differentiation and inhibited branching morphogenesis. Atypical cuboidal or columnar cells lined the lung periphery of SP-C/HFH-4 transgenic mice. T he atypical epithelial cells seen in the SP-C/HFH-4 mice expressed thyroid transcription factor-1 and hepatocyte nuclear factor 3 beta (HNF-3 beta). H owever, surfactant proteins SP-B, SP-C, and Clara cell secretory protein, n ormally produced by nonciliated epithelial cells in lung parenchyma were la cking. beta-Tubulin IV, a marker of ciliated cells, stained the atypical co lumnar cells produced by expression of high levels of the SP-C/HFH-4 transg ene. Ectopic expression of HFH-4 in developing mouse lung altered epithelia l cell differentiation and morphology, restricting the expression of marker s typical of nonciliated cells of the distal lung parenchyma. (C) 1999 Acad emic Press.