Papers published on the use of transgenic mice (as counted by searching the term transgenic mice on Medline) have grown from zero in 1980, when transgenic mouse was not yet in common use, to over 700 in 1992. During that 12-year period, perhaps thousands of different transgenic mice have been made in laboratories, often to be used in a few experiments before being discarded. Transgenic mice have become a major research resource, and applications of the transgenic approach have begun to infiltrate the world of biotechnology.

THE USES OF TRANSGENIC MICE

Thus far, a major use of transgenic mice has been to determine what DNA sequences regulate the expression of a gene in specific tissues or at specific times in development. Putative regulatory sequences from the gene of interest are attached to a reporter gene, which is microinjected into a mouse egg to create a transgenic animal, and tissue-specific expression examined. One can define promoter sequences, enhancer sequences, and locus-control elements, which together comprise the short-range and long-range sequences that drive spatial and temporal gene expression in mice.

Once specific promoter sequences directed at a particular tissue have been defined, they can be used to express many kinds of gene products in that tissue. The uses of directed expression of foreign genes are highly varied. Promoters can be used to express a toxin gene; wherever that gene is expressed, the cells will die, and the roles of these particular cells can be analyzed. Once the promoters are better defined, one can envisage using this technique to study the nervous system by ablating specific neurons in the developing brain and assessing the effect of such ablations on neural function.

One can also produce tissue-specific lineage markers by using a reporter gene like β-galactosidase, whose activity can be detected as blue-staining cells. The reporter gene can thus be used as a marker of lineage as one follows its presence in developmental or transplantation studies. Tissue-specific promoters have been introduced into many mice to drive activated oncogenes that produce tumors in particular tissues, such as mammary carcinomas, pancreatic tumors and lymphomas. These “oncomice” can be extremely useful for studying both the process of tumorigenesis and potential therapies for the tumors. Extension of the uses of tissue-specific expression of transgenes to animals other than mice opens up new commercial applications. Animals–perhaps cows, sheep, and pigs–can be used as factories to produce pharmaceutically important peptides. One approach is to direct gene expression to the milk proteins so that pharmaceutically important compounds are secreted efficiently into the milk, from which they can be isolated.

Transgenic mice can also be used to study gene function or to generate models for human genetic disease, provided that the desired effect can be



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