INSERTIONAL MUTAGENESIS AND MOUSE DEVELOPMENT

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The major aims of this proposal are to determine the phenotypic consequences of activating Src family kinases during development, and to understand the mechanisms by which these phenotypes arise. Src family kinases are negatively regulated by phosphorylation of a C- terminal tyrosine by two kinases, Csk and Ctk. Targeted disruption of Csk results in neural tube defects and embryonic lethality. In addition, a number of kinase substrates localized to focal adhesions, such as paxillin, and to the cytoskeleton, such as cortactin, become hyperphosphorylated in Csk- cells due to increased Src family kinase activity. To understand the consequences of activating multiple or individual kinases in development, mice will be derived carrying targeted mutations in the ctk gene, conditional mutations in the csk or ctk genes, and activating mutations in Src PTK genes. To test if alterations in cell adhesion might explain the phenotypes due to activation of Src family kinases, mice mutant for cortactin and paxillin will be generated. These mutations will be used to investigate the role of different cell adhesion mechanisms in the phenotype due to Src family kinase activation. This research should be useful to understand the role of kinase regulatory- and adhesion- pathways in normal embryonic development and in neoplastic transformation.