The forehead/winged helix transcription factors are known to play a major role in controlling of cell differentiation and tissue development. Two newly identified members of this gene family, namely Forkhead RElated ACtivator-1 and-2 [FREAC-1 (or HFH-8/FREAC-1) and FREAC-2], have been shown to express primarily in the lungs and placenta, and to a lesser extent in gastrointestinal (GI) tract. The results from our and other laboratories suggest that these two genes may be evolved from the same ancestor gene and share a common function in transcription activation of lung-specific genes. However, they may also exhibit distinct specificity of expression and regulatory function in the lungs. These understandings prompt us to hypothesize that a precise temporal-spatial expression of these two genes, which is under the control of other transcription factors, is critical for differentiation and interactions of lung epithelium and mesenchyme leading to lung morphogenesis. To test this hypothesis, the cell-specific expression of HFH-8/FREAC-1 and FREAC-2 genes in the developing and mature lungs will be determined by in situ hybridization in specific aim 1. Furthermore, a LacZ reporter gene, which codes for the E. coli enzyme beta- galactosidase, will be targeted into the mouse HFH-8/FREAC-1 and FREAC-2 loci under the transcriptional control of these two genes. This will allow us to further substantiate the results of in situ hybridization experiments. Mice deficient in these genes will then be generated for evaluation their function in lung development and gene expression. In addition, the cis-acting DNA element(s) controlling the tissue- and cell-specific expression of these two forehead genes will be determined by a classical promoter mapping analysis in specific aim 2. This information will further our understanding in the molecular mechanism and potentially the role of interactions between foregut endoderm and mesenchymal cells in lung morphogenesis and differentiation, as well as the pathogenesis of lung abnormalities and diseases resulting from disturbance of expression of these developmentally important genes following exposure to various environmental agents.
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