CORE--TRANSGENIC AND CHIMERIC MOUSE FACILITY

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications & trials

Abstract

The generation of transgenic mice through the introduction of foreign DNA into the fertilized mouse oocyte (1), has resulted in the development of an exciting array of new in vivo experimental models for the study of development, genetic disorders, transcriptional control of gene expression, tissue specificity of gene expression, and oncogenesis. For genes normally expressed in cells without adequate tissue culture counterparts, the generation of transgenic animals is the best current means of localizing gene control elements and studying gene functions (2). Additional techniques such as targeted oncogenesis (3), targeted ablation of cell linkages in the developing mouse (4,5), binary systems for regulating transgene expression (6), and homologous recombination using the Cre and loxP system from bacteriophage P1 (7) are refining the applications of transgenic technology. Gene-targeted (8,9) and transgenic mouse models have had a major impact on the understanding of many aspects of liver and digestive disorders. For example, an increased understanding of the enteric nervous system and insights into the pathophysiology of a ganglionic megacolon of Hirschspring's disease have accrued based upon the analysis of a varies of transgenic mouse models. These include mice with targeted disruptions of endothelin-3 or its receptor endothelin B, the tyrosine kinase RET and glial cell line-derived neurotrophic factor. These studies have led to the concept that at least two different mechanisms can cause aganglionosis of the terminal bowel (10). Similarly, deficiency of neuronal nitric oxide synthetase (nNOS) has been shown to induce to gastric dilatration and stasis in mice (11). Over-expression and deficiency of gastrin have been developed in transgenic mice confirming gastrin's role as a key regulator of parietal cell function, but also pointing to additional, unexpected functions such as colonic proliferation (12, 13). Experimental mouse models of immune imbalance leading to intestinal inflammation such as with the interleukin-10 null mice (14) or TNF over-expressing mice (15) begin to provide mouse models for inflammatory bowel diseases such as Crohn's disease. Intestinal epithelial apoptosis can be studied in transgenic mouse models such as p53 null mice, but not in tissue culture models (16). Studies of transgenic mouse lines have contributed to an understanding of the mechanisms involved in the initiation of liver regeneration and have provided critical information about the gene regulation and function of many liver- expressed genes (17). It is clear that the complexity of the digestive organs is well suited to physiologic analysis in transgenic and targeted mouse models. The primary function of the Transgenic and Chimeric Mouse Facility is to provide a centralized laboratory that will generate infection-free, transgenic founder or chimeric strains of mice carrying transgenes or gene knock-outs of specific interest to individual projects in the Center. The centralization of these technically demanding procedures results in enhanced efficiency and cost reduction for reach project. The generation of mouse models facilitates collaborations and interactions among the Center members as well.