Lung development depends upon epithelial-mesenchymal interactions. These interactions appear to mediate both morphogenesis and differentiation. It is suggested that mesenchyme-derived signals provide instructions for both epithelial morphogenesis and differentiation into alveolar type II cells and production of pulmonary surfactant. When, where and how mesenchyme-directed instructions mediate morphogenesis and differentiation during lung development is the focus of this proposal. Our hypothesis is that glucocorticoid-responsive mesenchyme cells mediate instructions for parenchymal morphogenesis during the embryonic period, and subsequently mediate epithelial differentiation into type II cells during the fetal period of mouse embryogenesis (circa 13-17-days gestation). To test our hypothesis, we propose to use the model of mouse (B10 and B10.A congenic strains) lung development in vivo and in vitro using a serumless, chemically-defined medium. Investigations include a description of temporal and spatial changes in basal lamina constituents (e.g. type IV collagen, laminin, BM-proteoglycans and fibronectin), epithelial cytoskeletal constituents (e.g. cytokeratin, keratin and tubulin), and mesenchymal constituents [e.g. glucocorticoid receptor activity and fibroblast pneumonocyte factor (FPF) antigens] during lung morphogenesis and differentiation. We propose to test specificity of instructive mesenchyme-epithelial interactions during development in vitro using iso- and heterochronic, and homologous and heterologous tissue recombinations. We propose to determine how mesenchyme instructs epthelial morphogenesis as well as differentiation into type II cells. Finally, we propose to """"""""dissect"""""""" instructive and permissive epithelial-mesenchymal interactions from hormone-enhanced interactions using serumless, chemically-defined medium. Methods include indirect immunofluorescence microscopy, autoradiographic localization of [3H]-dexamethasone binding to lung tissues, [35S]-methione incorporation into epithelial specific differentiation antigens, [3H]-choline incorporation into pulmonary surfactant, and immunochemical and immunocytochemical localization of specific antigens associated with lung parenchymal epithelia, basal lamina and adjacent pulmonary mesenchyme during lung development. These studies should enhance understanding of instructive and permissive functions of mesenchyme and glucocorticoids during development, implications of immunogenetics, and the processes of fetal lung maturation in the mouse lung.
| Jaskoll, T F; Johnson, R; Don, G et al. (1986) Embryonic mouse lung morphogenesis in serumless, chemically-defined medium in vitro. Prog Clin Biol Res 217A:381-4 |
| Slavkin, H C; Jaskoll, T F; MacDougall, M et al. (1986) Hormonal and non-hormonal features of selected epithelial-mesenchymal interactions during development. Prog Clin Biol Res 226:93-102 |
