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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Cellular Biology and Physiology Subcommittee 1 (CBY)
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Vanderbilt University Medical Center
Anatomy/Cell Biology
Schools of Medicine
United States
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Weaver, Molly; Batts, Lorene; Hogan, Brigid L M (2003) Tissue interactions pattern the mesenchyme of the embryonic mouse lung. Dev Biol 258:169-84
Liu, Yuru; Jiang, Haiyan; Crawford, Howard C et al. (2003) Role for ETS domain transcription factors Pea3/Erm in mouse lung development. Dev Biol 261:10-24
Kulessa, Holger; Hogan, Brigid L M (2002) Generation of a loxP flanked bmp4loxP-lacZ allele marked by conditional lacZ expression. Genesis 32:66-8
Liu, Yuru; Hogan, Brigid L M (2002) Differential gene expression in the distal tip endoderm of the embryonic mouse lung. Gene Expr Patterns 2:229-33
Fujiwara, T; Dunn, N R; Hogan, B L (2001) Bone morphogenetic protein 4 in the extraembryonic mesoderm is required for allantois development and the localization and survival of primordial germ cells in the mouse. Proc Natl Acad Sci U S A 98:13739-44
Weaver, M; Dunn, N R; Hogan, B L (2000) Bmp4 and Fgf10 play opposing roles during lung bud morphogenesis. Development 127:2695-704
Furuta, Y; Lagutin, O; Hogan, B L et al. (2000) Retina- and ventral forebrain-specific Cre recombinase activity in transgenic mice. Genesis 26:130-2
Lawson, K A; Dunn, N R; Roelen, B A et al. (1999) Bmp4 is required for the generation of primordial germ cells in the mouse embryo. Genes Dev 13:424-36
Weaver, M; Yingling, J M; Dunn, N R et al. (1999) Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development. Development 126:4005-15
Hogan, B L; Yingling, J M (1998) Epithelial/mesenchymal interactions and branching morphogenesis of the lung. Curr Opin Genet Dev 8:481-6

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