Lung buds are composed of epithelial tubules surrounded by mesoderm. The presence of the mesoderm is essential for development of the bronchial tree. The interface between epithelial cells and mesenchyme seems to be an important site for control of lung morphogenesis. This area contains a basement membrane derived from epithelium and an extracellular matrix from mesenchyme which consists of interstitial collagen, fibronectin (FN), sulfated proteoglycans and elastin. This matrix appears to be critical for epithelial branching. Studies of a collagen (l)- deficient mouse mutant indicates that collagen (l) is not required for lung development. Mutants are not available for the other matrix components and studies relating these molecules to lung development have relied on examining their expression during lung development. Expression of both FN and its cell surface receptor (FNR) is activated with the onset of branching but is subsequently reduced in adult lung suggesting a role for FN/FNR-mediated cell adhesion and migration during branching.
The aim of this proposal is to study the expression of FN and the FNR in lung development. Antibodies to these molecules will be used for immunohistochemistry and cDNA probes will be used for in situ hybridization in sections of mouse lung at different stages of gestation. Regulation of FN and FNR expression by growth factors and proto-oncogenes will be examined in cultures of lung- derived cell lines to gain information about how these genes may be regulated during lung development. TGF-beta 1, EGF and PDGF have already been demonstrated to induce expression of FN and FNR (only TGF-beta 1 has been examined for FNR). The spacial and temporal pattern of expression of these regulatory molecules will be followed during lung development and compared to expression of FN and FNR. The mechanism of action of TGF- beta 1 will be examined. This growth factor also induces expression of collagens and sulfated proteoglycans, is involved in wound healing and is necessary for differentiation of lung epithelial cells. It is localized at the epithelial-mesenchymal junction in developing lung. Nothing is known of the mechanism of how binding of TGF-beta 1 to a cell surface receptor alters events in the nucleus. We have identified a DNA regulatory element (an NF-1 binding site) in the FN promoter that mediates the effect of TGF-beta 1 on transcription. Studies of the effect of TGF-beta 1 on the NF-1 protein (the nuclear transcription factor that interacts with this regulatory site) should provide information on the TGF-beta 1 second messenger.
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