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Of Mice and Men – Transgenic Mouse Models

July 15, 2006

Introduction

Most serious illnesses are complex diseases. Complex diseases are caused by a variety of interacting genetic and environmental elements. Because of their entangled genesis, complex diseases are difficult to understand and treat. For example, diet, exercise, other lifestyle changes, and hereditary factors can all contribute to the development of heart disease.

The recombinant DNA revolution in the 1970s provided the technology for biomedical researchers to investigate the genetic and molecular basis for complex human diseases such as heart disease. Molecular genetic techniques enable scientists to create animal models that mimic various aspects of a disease. Studying the effect of highly specific genetically engineered changes offers insight into the genetic and molecular mechanisms that underlie the onset of disease.

Transgenic Mice in Cardiovascular Disease Research

Recently, the mouse has emerged as the most prevalent experimental model for cardiovascular research. Formerly, larger mammals such as pigs and rabbits had been the preferred experimental animals. Many researchers perceived the differences in cardiac size and morphology to be so large as to preclude the use of mice as a relevant experimental model for human cardiovascular disease. As the comparative ease in applying recombinant DNA technology in mice (relative to other species) became apparent, the popularity of murine experimental models grew. The advantages of short gestation periods, cost-effective maintenance, and a well-characterized genome make the mouse the ideal experimental model. Animal models are useful not only to elucidate the molecular mechanisms that underlie heart disease, but also to test experimental therapies. Recently, the miniaturization of technologies for measuring cardiac endpoints has vastly increased the variety of cardiovascular traits that can be modeled. In 1992, a mouse deficient in apolipoprotein E, the apoE -/- mouse, was generated as the first mouse-line with a stable genetic background that developed spontaneous arterial lesions and coronary artery occlusion (2,3). Since that time, the size and scope of cardiovascular research on genetically engineered mouse models has grown prodigiously.

Transgenic Mice in Psychiatric Research

Psychiatry remains the branch of medicine that has had the least success with developing animal models. Traditionally, rats have been standard test animal for psychiatric research, but recently the popularity of transgenic mice in other areas of medicine has shifted animal research towards mouse models. Most of the focus has been towards developing robust behavioural models of anxiety-related behaviors. Most models rely on evaluating behavioral reaction to stressful situations. Because of the overwhelming, and irreducible complexity of the causes of psychiatric illnessses, researchers have faced difficulty creating translational models for depression or any other mental illness. Consequently the focus has shifted towards generating ‘endophenotypes’ of disease. This means that researchers are shifting their focus towards recreating specific features of disease, with specific genetic or neurological causes.

Because of the wide gulf between human and mouse ‘lifestyles’, I am unconvinced about the degree of usefulness in this approach to psychiatric research – especially because the neurobiologial and genetic bases for psychiatric diseases are still so poorly understood. Future progress in the use of mouse models depends upon improvements in technology for behavioral assessments. Only with detailed, sophisticated and (most importantly) standardized assays for evaluating behavior in mice will the use of mouse models in psychiatric research fully mature.

Limitations

Psychiatric and cardiovascular disease research represent the two ends of the spectrum with regards to successful incorporation of transgenic mouse models. There remain, however, some concerns that are common to all fields of mouse research. For example, recent evidence suggests that researchers should exercise caution when drawing conclusions from mouse research as the genetic background of specific strains will affect the severity of the phenotype that is expressed (epigenetics anyone?).

Another problem is that position-dependent non-specific effects can be caused when transgenes are insterted randomly into the genome and interrupt existing genes – resulting in an insertion mutation.

Also, transgenic expression of presumably <ectopic proteins> can also compromise results. For example, it has been shown that transgenic expression of <GFP>, normally considered non-reactive, can have diverse phenotypic effects (29). Perhaps even more worrying are the consequences of gene redundancy and compensatory responses (30). Evidence indicates that the molecular events under investigation are part of immensely complex biological processes governed by multiple genetic and molecular influences. Crudely knocking out or overexpressing a protein may activate normally dormant compensatory mechanisms. In such a scenario, the phenotype expressed would not be indicative of a loss of actual function. This sort of difficulty will be eliminated with the emergence of more refined genetic technologies that will allow for more cell type-specific and time-governed genetic manipulation.

Future Directions

There are several collaborative projects underway to improve the resources available to researchers using genetically manipulated models. Two of the most ambitious are the Mouse Phenome Project undertaken by Jackson Laboratories (Bar Harbor, Maine; http://www.jax.org) and a Complex Trait initiative begun by Complex Trait Organization (Memphis, Tennessee; http://www.complextrait.org). The Mouse Phenome Project is an attempt to create a public database of detailed phenotypic data on the most common inbred strains. They also hope to generate new lines that closely represent human disease through directed breeding based on the natural variation among extant mouse strains and chemically induced, whole-genome mutagenized mice. The creation of the database and the generation of new models will allow researchers to make informed decisions about what background to use for genetic manipulation when making new models. The information will also help scientists sort out strain-dependent effects when interpreting data. Geneticists at the Complex Trait Organization want to locate genes involved in complex traits by creating 1000 new lines of “recombinant inbred” mice. Each line would be a combination of eight existing strains; the scientists would outcross the mice for four generations and then breed brother-sister pairs for 20 generations to create inbred lines. Researchers hope the new lines will be able to reveal the genes that interact to produce complex, non-Mendelian traits and represent the variation in natural mouse populations.

The emergence of functional genomics presents a great new opportunity for research involving genetically manipulated mouse models. New technologies such as gene microarrays let researchers look at the activation of thousands of genes at any given time. This is especially advantageous in the study of complex polygenetic diseases such as cardiovascular disease. As this and other functional genomic technologies mature, researchers will have powerful new tools to examine complex genetic interactions.

Down Syndrome Mouse

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