Genetic manipulation of the mouse genome

Perhaps the most important advantage to using the mouse for biomedical research is the ability to experimentally manipulate the mouse genome. Genes can be injected directly into the fertilized egg of a mouse creating what is known as a transgenic animal. This approach allows scientists to create new models and experimental tools based on the manipulation of specific genes thought to be important in the pathology of certain diseases. 

Subsequently, scientists developed techniques that allowed them to specifically target genes within the mouse genome – so-called “knockouts” – that further enhanced their biological toolkit. The foundation for this technique was laid by the pioneering work of Leroy Stevens at The Jackson Laboratory, who discovered stem cells in tumors in the 1950s.  Others subsequently demonstrated that pluripotent embryonic stem (ES) cells could be grown in culture, which led to the finding that mouse genes could be altered in such cells by homologous recombination or targeting. Thousands of mouse genes have been targeted in this fashion and the Knockout Mouse Project (KOMP) and the International Knockout Mouse Consortium (IKMC), have made substantial progress toward the ambitious goal of knocking out all of the genes in the mouse genome. A program to turn these targeted ES cells into mice has begun and these ‘knockout’ mice will be phenotyped within the next few years, providing a comprehensive resource for biologists seeking to understand the genetic basis of mammalian biology and disease progression.

And the toolkit continues to expand. The gene targeting technology used to create knockouts can be employed to replace mouse genes with genes that encode fluorescent proteins providing researchers with powerful tools to image and track specific cell types. Mouse genes can be replaced with human genes to study gene function or to produce more human-like model systems in the mouse. For example, the so-called “NOD scid gamma” mouse developed by Leonard Shultz at The Jackson Laboratory lacks mature T or B cells, and functional NK cells; is deficient in cytokine signaling; and can accept transplantation of virtually any human tissue.  New technologies allow scientists to not only knock out genes of interest, but to do so in a specific tissue at a specific time, refining their ability to investigate crucial biological questions. As these tools continue to be developed, scientists will expand their ability to model human disease more accurately, as well as directly test their theories using the mouse.

Knockout Mouse Project

The Jackson Laboratory is part of an international effort to establish a global resource of knockout mice and related database of gene function.

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