Caveats of Gene-Targeted and Transgenic Mice

Genetic modifications in the germ line of mice help in the study of gene function in vivo. This has occurred as a result of two major discoveries. The first was the ability to isolate from the inner cell mass of mouse blastocysts totipotent embryonic stem (ES) cells. In particular, they have aided the understanding of several disease processes and hence the development of possible treatments that will benefit humankind. However, the observed phenotype of gene-targeted mice may be dependent on numerous other factors in addition to the specific genetic modification. The second discovery was the development of methods that allowed the modification of specific genes within the ES cells by homologous recombination in a process known as gene targeting. The genetic background influences the expression of a transgene. Epigenetic mechanisms can control gene expression. At times, subtle interactions between the gene of interest and the host genotype may influence the observed phenotype, including the possibility of previously unconsidered epigenetic mechanisms. Attempts at temporal control of gene expression have also been made using different chemicals or hormones to regulate function of the promoter of a transgene. The transgenes are therefore not truly tissue or temporal specific, since they can be expressed in the wrong tissue or at the wrong time. Many factors influence the resultant phenotype after the manipulation of a specific gene either by gene targeting or by overexpression. The ability to switch a gene function on and off at will in individual animals-in a temporal- and tissue-specific manner and in a variety of genetic (and epigenetic) backgrounds-should enable a more informative approach to the identification of gene function in health and disease.