GENE AND TRANSGENE REGULATION IN THE DEVELOPING MOUSE

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Lens oncogenesis and differentiation. A dormant oncogene has been activated in the transgenic mouse via the prokaryotic, site-specific recombinase CRE. The onset of oncogene expression has been directed to coincide with specific stages of lens development. Lens fiber cells can thus be immortalized at distinct stages along their pathway to terminal differentiation. Expression of nm23 during mouse development. The expression of nm23 has been described as a marker of non-metastatic growth properties of certain rodent and human tumors. During mouse development, we detect high levels of the nm23 gene during organogenesis. Expression appears confined to epithelial tissues, and is especially prominent between the onset and the terminal phase of differentiation. This expression pattern correlates well with the inverse relationship between nm23 expression and invasiveness observed in tumors of epithelial origin. Role of the T-cell receptor (TCR) zeta chain in thymocyte development. The TCR-zeta chain is an essential subunit of both the T-cell antigen receptor complex and certain Fc receptors. In both contexts, zeta in required for receptor surface expression and ligand-mediated signal transduction. To examine the role of TCR-zeta in T-cell ontogeny, transgenic mice expressing high levels of full-length or mutated forms of the zeta chain have been generated and analyzed. The results suggest that 1) zeta-mediated signalling pathways control early thymocyte developmental events such as TCR alpha and beta gene rearrangement, and 2) surface expression of TCR complexes during development is controlled by the level of intracellular zeta chain. Animal modal of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase (GC) gene. In a large collaborative experiment, we generated a null allele of GC in murine embryonic stem cells by inserting a neomycin resistance gene in the chromosomal target gene. Mutant embryonic stem cells were injected into normal blastocysts, and a chimeric germ line mutation was obtained. Mice homozygous for the GC mutation have less than 4% of normal GC activity, die shortly after birth and show a lysosomal storage disorder that resembles that of Gaucher patients. The animals will therefore be valuable for investigating the pathogenesis of the human disease and for evaluating therapeutic approaches.