The long term goal of this proposal is to understand the molecular and genetic mechanisms that regulate cell migration and epithelial-mesenchymal transitions in early postimplantation mouse embryos. In this proposal, these questions will be studied by constructing and analyzing targeted null mutations of the genes sna and slug. These genes are mouse homologs of the Drosophila gene snail, which encodes a zinc finger protein that is required zygotically for mesoderm formation during Drosophila embryogenesis. Analysis of snail homologs in other vertebrates suggests that snail family genes are important in regulating adhesive interactions between cells, such as the interactions involved in the epithelial-mesenchymal transition required for the generation of both the mesoderm and the neural crest.
The specific aims of this proposal are: 1) Test the hypothesis that the sna and slug genes are essential for normal embryonic development, and that embryos homozygous for null mutations of these genes will show defects in delamination and migration of tissues such as mesoderm, parietal endoderm and neural crest, by generating and characterizing mice containing null mutations in these genes. 2) Assess the cell autonomy of sna and slug mutant phenotypes by constructing embryonic stem cell lines homozygous for sna and slug mutant alleles, and analyzing the behavior of these cells in chimeric embryos. 3) Determine whether the sna and slug genes in mice are in part functionally redundant by constructing and analyzing sna/slug double mutants. 4) Determine the DNA binding site specificity of recombinant SNA and SLUG proteins, and generate antibodies specific for these proteins. 5) Clone additional members of the snail gene family, and characterize their expression in both wild type embryos and in sna and slug mutant embryos.
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