Research Paper On Transgenic Animals

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One of the major difficulties in aging research (especially aging research using higher organisms) has been the ability to test experimentally whether a change in a specific gene or physiological process is involved in aging. For the most part, investigators have been forced to conduct correlative experiments with animals, for example, correlating changes in a process or a macromolecular entity to changes with aging. Although correlative experiments are important because they define what changes occur in an organism with age and they provide investigators with information that can be used to support or refute various theories of aging, these types of experiments do not allow one to test directly the role of a specific gene in aging or a theory of aging. With the advent of recombinant DNA technology and the ability to genetically engineer mice, investigators now have an experimental system whereby a specific gene or process can be altered in rodents and the effect of this alteration on aging can be studied. Using this unique system will make it possible to probe more directly the biological mechanism(s) underlying the aging process. In this article, we discuss the current experimental methods used in producing transgenic mice and the potential problems that investigators should consider when developing transgenic mouse models to study aging.

Methods for Producing Transgenic Mice

Transgenic animals are defined as animals that either carry a fragment of foreign DNA stably integrated into the genome of the organism or have a portion of the genome deleted or mutated. In general, these animals are produced so that the genetic alterations are stably transmitted to the progeny through the germ line. The first report describing the production of transgenic mice was published in 1980 ( Turrens and Boveris 1996 ). Subsequently, transgenic mice have been used extensively to study a variety of biomedical questions (for review see Cruse and Lewis Jr. 1994 ; Ho 1994 ; Knapp and Kopchick 1994 ; Koretsky 1992 ; Montoliu 1994 ; Norwood and Gomez 1994 ; Rusconi 1991 ; StC. Sinclair 1995 ; Sullivan and others 1993 ; Wagner and others 1995 ). In this article, we discuss 2 experimental approaches in which transgenic mice can be used to study aging: (1) gain in function, and (2) reduction or loss of function.

Transgenic mice have been generated using 3 techniques ( Hogan and others 1994 ). The most straightforward and widely used method is the introduction of DNA into the nucleus of a cell. This method involves the microinjection of exogenous DNA into the pronuclei of fertilized eggs as shown in Figure 1 . The injected eggs are then transferred to the oviduct of a pseudopregnant female and allowed to develop to term. The integration of the exogenous DNA into the genome of the fertilized egg is believed to occur through the normal process of chromosomal breakage and repair, occurring randomly in the genome. The exogenous DNA is often integrated as multiple copies into 1 site in a head-to-tail array; however, multiple integrations also can occur. In this method of producing transgenic mice, it is important that the random integration occurs in the 1-cell stage so that the exogenous DNA is integrated into the genome of all cells in the organism, especially the germ cells. When integration occurs at later stages, mosaic animals are produced in which the exogenous DNA is confined to specific developmental compartments or cell lineages.

Figure 1.

Summary of the method used in producing transgenic mice by the microinjection of exogenous DNA into the pronuclei of fertilized eggs.

Figure 1.

Summary of the method used in producing transgenic mice by the microinjection of exogenous DNA into the pronuclei of fertilized eggs.

Transgenic mice also have been produced by the infection of early embryos with recombinant retroviruses carrying an exogenous gene. This method has an advantage in that only 1 copy of the provirus is found at the chromosomal integration site; however, the technique has several limitations. For example, the retroviruses may not uniformly infect all cells in early embryos, therefore the frequency of germ line transmission is relatively low. In addition, the expression of genes introduced in retroviral vectors is often low, and only a relatively small fragment of the DNA (smaller than 10 kb) can be cloned into the retroviral vector.

The third method for producing transgenic mice takes advantage of the pluripotential capacity of embryo-derived stem (ES1) cells. In this method, the ES cells in culture are transformed using conventional gene transfer techniques, and the transformed cells are reintroduced in early blastocysts, which are transferred to appropriately timed pseudopregnant females. The transformed ES cells contribute to the development of a chimeric offspring; one can identify chimeric mice in which the ES cells have contributed to the germ line. This method allows an investigator to preselect the desired genotype or phenotype in the cultured ES cells. Although investigators have used ES cells to produce transgenic mice that express specific genes, this method is used primarily to target a transgene construct to a predetermined chromosomal locus through homologous recombination, thus producing transgenic mice that carry a mutation in a specific gene. These mutations can inactivate the gene or alter the function of the corresponding protein. Thus, the ES cell method has several advantages over the other techniques for producing transgenic mice, although the culturing and maintenance of fully totipotent ES cells are technically demanding.

Use of Transgenic Animals Showing Gain in Function in Aging Research

The majority of studies with transgenic mice have employed models in which the animals have been engineered genetically to overexpress a specific gene product in cells that either normally express or do not express the gene. Such transgenic mice have been produced almost exclusively by the microinjection of a specific transgene into the pronuclei of fertilized eggs as shown in Figure 1 . Below we discuss several factors that should be considered when producing transgenic mice for aging studies by this technique, including the transgene construct, the chromosomal site of integration, the strain of mice, and the use of transgenic rats.

Transgene Construct

Transgenic mice have been produced using DNA fragments containing an entire gene, that is, both the exons and introns of the gene of interest as well as the 5'-flanking enhancer/ promoter sequences that regulate the transcription of the gene. However, investigators more commonly use chimeric transgenes that are made up of several components as shown in Figure 2

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