The proposal focuses on the process of branching morphogenesis by pursuing the roles of the BMPs, FGFs, hedgehogs, and Wnts, that are expressed in the distal tips of lung buds, and which are sites of active branching. The four specific aims are: (1) to determine a high-resolution three-dimensional map of the expression of these signaling molecules during branching morphogenesis; (2) to determine the role of BMP4 in lung development by using tissue specific gene targeting to inactivate BMP4 in the lung, and to use a tissue specific promoter to drive expression of dominant negative forms of BMP receptors; (3) to investigate the roles of sonic hedgehog and FGF10 in epithelial mesenchymal interactions using in vitro assays to complement gene disruption analyses (Shh by Beachy et al., FGF10, being performed in Japan); and (4) to investigate the role of Wnt7b in lung by overexpression in transgenic mice initially, then by deletion specifically in the lung if the Cre/lox approach works for BMP4.
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