Role of the Int-3 Oncogene in Mammary Gland Development and Tumorigenesis

The overall objective of my research project, was to define the biological function of the mouse Notch4 gene. Based on genetic analysis in Drosophila and C. elegans, Notch proteins have been demonstrated to regulate cell fate decisions during development. Using in vitro and in vivo models, my work has provided evidence that supports the model that Notch4 modulates cell fate decisions in the mouse mammary gland and developing endothelium. Branching morphogenesis of the mouse mammary epithelial TAC-2 cell line was used as an assay to examine the role of Wnt, HGF, TCF-beta and the Notch receptors in branching morphogenesis. Rat brain micro vessel endothelial cells were used as a model system to study the role of Notch4 and Jagged-1, a putative Notch ligand, in endothelial cell differentiation. To study the in vivo role of Notch4 in endothelial cell development, homologous recombination in embryonic stem cells was used to drive expression of Notch4 to endothelial cells during embryonic development. Activating mutations in the Notch4 gene disrupt the normal architectural patterns that are required for proper development of these tissues. These observations support a role for Notch signaling in cell fate determination during mammary gland and endothelial cell differentiation.