Abstract
The use of genetically engineered mice in biomedical research is extensive and has led to notable advances in the understanding of disease pathogeneses; in fact, the National Medal of Science was awarded this year to Dr Ralph Brinster, VMD, PhD, for his contributions in this field. Veterinarians have been and continue to be on the forefront of evaluating genetically engineered mice. However, the histopathological interpretation of findings in these modified mice is deceptively intricate.
Many pathologists wonder what is so difficult about phenotyping genetically engineered mice: all you have to do is look at enough mutant and control mice and note the histological differences. If only it were that simple! Even in the best of circumstances—appropriate numbers of mutant mice with only 1 gene mutation and the littermate controls—interpreting the findings can be daunting in part because of unanticipated effects (eg, leaky promoters, neomorphic or hypomorphic allelic expression instead of allelic deletion, microbial infections) and genetic dissimilarity between ES cells and the backcrossing strains. The variation in background lesions and responses to infectious agents or genetic manipulation between inbred laboratory mouse strains can be extensive; the complexity of the genetic variation between inbred strains of mice cannot be underestimated.
Unfortunately, training in mouse histology, histopathology, and physiology relative to strain variation, normal background findings, sexual dimorphisms, aging lesions, and embryonic development in typical pathology residency programs has not kept pace with the use of genetically engineered mice in research. As pathologists, we rely on images of both normal and abnormal tissues to expand our ability to recognize patterns and interpret findings. Pathologists who work with mice, particularly genetically engineered mice, learn extensively by experience and word of mouth as well as by scattered mouse pathology texts and Websites. Compounding the predicament of accurate mouse phenotyping is the shortage of veterinary pathologists (mouse pathologists) and physician pathologists with whom scientific researchers may collaborate. This special issue on genetically engineered mice touches on some of the issues facing pathologists as we work with these mice. The goal of this issue is in part to highlight and discuss some of the complexities of evaluating the histopathological findings as a result of gene modification in mice. The issue starts with the history of genetically engineered mice and strategies for designing phenotyping studies. Following this are articles with specific considerations for the evaluation of genetically engineered mice from the embryo to the aged, including methods, new mouse models of disease, and valuable reference publications for the veterinary pathologist. We hope that this issue, which includes many color images as well as a supplement of selected on-line scanned slides (http://vet.sagepub.com and click on SAGEscope), will serve as a resource for pathologists and other researchers alike in their search to better understand gene function and disease.