GENE AND TRANSGENE REGULATION IN THE DEVELOPING MOUSE

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Lens oncogenesis and differentiation. We generated mice that carry copies of a dormant transgene encoding the SV40 tumor antigens. The transgenes are specifically targeted to the lens and contain features that render their expression dependent on the action of Cre, a site- specific bacteriophage DNA recombinase. Timing of oncogene activation was controlled by making Cre available either prior to, or coincident with, the onset of primary fiber differentiation in the embryonic lens vesicle. Early expression of Cre resulted in oncogene activation in undifferentiated lens epithelial cells that rapidly proliferated inside the lens capsule. By contrast, when Cre accumulation was delayed to coincide with the onset of primary lens fiber differentiation, SV40 oncogenes were activated in cells that had begun to elongate and to accumulate lens-specific crystallins. During subsequent proliferation inside the lens capsule, transformed progeny cells maintained the profile of fiber differentiation that their parent cells had acquired at the time of oncogenic conversion. Our findings show that the differentiated state of the primary target cell is an important parameter of subsequent lens oncogenesis, and that an intact lens capsule can restrict invasive neoplastic growth. The analysis of lim gene function has become a new focus of research. Lim genes encode part of a network of functions involved in pattern formation and cell specification during metazoan development. Their intricate regulatory potential is indicated by the fact that they contain three adjacent regulatory regions, two lim domains and one homeo domain. We have begun our work on the lim genes by cloning and sequencing lim1, a homolog of the Xenopus laevis Xlim1 gene. The gene has been extremely well conserved during evolution, Transcripts are detected in the developing excretory system and in the central nervous system. Role of the Zeta-family signaling molecules in T cell development. The Zeta-family dimers are a group of structurally and functionally related proteins that are expressed as subunits of the T-Cell antigen receptor complex or as subunits of certain Fc receptors. In both contexts, they facilitate ligand-mediated signal transduction by coupling the surface receptor to intracellular signaling pathways. We have begun to analyze the role of the Zeta- family dimers in T-cells ontogeny by: 1) generating transgenic mice that overexpress each of these molecules or the overexpress mutated forms of Zeta, and 2) generating mice that lack Zeta, the predominant member of this group, by homologous-recombination. Our results suggest that the Zeta family dimers can perform complementary functions in development but that critical thymocyte signaling pathways are differentially responsive to these signaling molecules.