The long term goal of this proposal is to understand the multiple roles that the Notch signaling pathway plays during embryonic development in mammals. The components of the Notch signaling pathway constitute an evolutionarily-conserved set of proteins that are essential for proper embryonic development in numerous organisms. Mutations in components of the Notch pathway also contribute to human disease. In Drosophila, the Notch gene encodes a large transmembrane receptor that, at the extracellular surface of a cell, interacts with membrane-bound ligands encoded by the Delta and Serrate genes. Work by us and by others has determined the mutant phenotypes for all of the known receptors and ligands of the Notch pathway in mice. This groundwork has permitted us to identify the Notch family receptors with the most severe and earliest-acting mutant phenotypes. Embryos homozygous for a null mutation of the Notch1 gene have the most severe phenotype of all the Notch receptor mutants.
The aims of this proposal are to: 1) construct lacZ-marked embryonic stem cell lines homozygous for a null mutation of the Notch] gene, and study the behavior of these mutant cells in chimeras made with wild type mouse embryos; 2) generate an allelic series of Notch1 mutant alleles; 3) assess dosage- sensitive effects of mutations of the Notch1 and Jagged2 genes on differentiation of sensory hair cells in the inner ear; 4) create missense alleles of the Notch3 gene (similar to those observed in a human disease syndrome) to determine if they cause gain of function mutations. These studies will further our understanding of the roles of the Notch signaling pathway in mammalian development. The information gained by analyzing this model system should be applicable to the study of both normal and abnormal human development.
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