The aim of this proposal is to elucidate the role in mammalian development of the gene product known as Bone Morphogenetic Protein-4 (BMP-4). This secreted protein is a member of the TGFbeta superfamily and is closely related to Drosophila Decapentaplegic (DPP). BMP-4 RNA is first expressed in the posterior ventral mesoderm of the early neurula stage mouse embryo, and then later in many regions where mesenchymalepithelial interactions are required for morphogenesis. There is also strong genetic and immunocytochemical evidence that, in Drosophila, DPP acts as an intercellular signaling molecule, transferring positional information from the mesoderm of the larval midgut to the underlying endodermal cells. A variety of genetic and biochemical techniques will be used to test the hypothesis that BMP-4 plays a similar role in mediating inductive tissue interactions in the mammalian embryo. Homologous recombination in embryonic stem (ES) cells will be used to introduce null mutations into the BMP-4a gene on Chromosome 14 and the BMP-4b gene on the X chromosome. Chimeric mice will be produced by blastocyst injection and used to generate hemizygous, heterozygous and homozygous mutant mice. These will be analyzed for defects in morphogenesis and pattern formation. A similar analysis will be made of transgenic mice in which BMP-4 is misexpressed in ectopic sites in the embryo and adult under the control of heterologous gene regulatory sequences. For studying the synthesis, secretion and localization of BMP-4 in vivo and in transfected cell lines in vivo, polyclonal rabbit antibodies will be prepared against both the variable and conserved regions of the protein. Finally, the effect of BMP-4 protein will be investigated on Xenopus and chick embryos in vivo. Together, these different approaches will throw light on the role of BMP-4 in morphogenesis and pattern formation in the embryo, and provide basic information relevant to congenital defects and teratogenesis in humans.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD028955-01
Application #
3330471
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1992-05-01
Project End
1997-04-30
Budget Start
1992-05-01
Budget End
1993-04-30
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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
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
Weaver, M; Dunn, N R; Hogan, B L (2000) Bmp4 and Fgf10 play opposing roles during lung bud morphogenesis. Development 127:2695-704
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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