During early mammalian development, a sequence of morphogenetic movements define the anterior-posterior body axis, create the germ layers, organize the midline, and elongate the embryo to generate the correct spatial arrangement of tissues and organs. A forward genetic screen has successfully identified a large number of novel chemically-induced mutations that disrupt morphogenesis of the embryo. SNP-based mapping and next generation sequencing have made it possible to rapidly identify the genes responsible for the developmental defects of the mutants. Additional morphogenesis mutants will be identified in focused, reporter-based screens. Building on the mutations that have been identified, experiments will define the mechanisms that control two key events in early development, establish the anterior-posterior body axis, and the epithelial-to-mesenchymal transition (EMT) that generates the three layers of the embryo during gastrulation. Experiments will test whether elevated Wnt signaling is necessary, but not sufficient, to generate ectopic body axes, and whether Axin1, p120-catenin and Usp8 work together to restrict the ability of cells in the epiblast to give rise to the pluripotent cells ofthe primitive streak. Data suggest that although the EMT involves loss of apical-basal polarity, a set of apical-basal polarity proteins is required for the gastrulation EMT. To understand the paradoxical requirement for apical-basal polarity in the EMT, conditional gene deletion will be used to determine which cells require the activity of polarity proteins and fluorescently tagged apical proteins will be used to follow the fate of apical junction proteins during the EMT. The proposed studies will define the genes and mechanisms that are responsible for congenital malformations such as situs inversus, microcephaly, and heart defects. The same genes discovered for their role in embryonic morphogenesis are likely to be critical importance in tumorigenesis and metastasis.
Normal mammalian development is regulated by intercellular signals that direct cell migration and cell rearrangements. Genetic experiments will identify and characterize genes that couple signaling molecules to cell behavior that are important in birth defects. Based on past experience, the genes identified in the embryo will play important roles in tumorigenesis and metastasis.
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